US 20070O82347A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2007/0082347 A1 Lanchbury et al. (43) Pub. Date: Apr. 12, 2007

(54) VARIANTS AND USE THEREOF on Jun. 8, 2005. Provisional application No. 60/698, 179, filed on Jul. 11, 2005. Provisional application (75) Inventors: Jerry Lanchbury, Salt Lake City, UT No. 60/698,211, filed on Jul. 11, 2005. Provisional (US); Alexander Gutin, Sandy, UT application No. 60/741,173, filed on Nov. 30, 2005. (US); Andrey Zharkikh, Salt Lake Provisional application No. 60/741,274, filed on Nov. City, UT (US); Julia Reid, Salt Lake 30, 2005. Provisional application No. 60/741,350, City, UT (US); Kirsten Timms, Salt filed on Nov. 30, 2005. Provisional application No. Lake City, UT (US); Susanne Wagner, 60/741,351, filed on Nov. 30, 2005. Salt Lake City, UT (US); Ann-Marie Woodland, Roy, UT (US) Publication Classification Correspondence Address: (51) Int. Cl. MYRAD GENETICS INC. CI2O I/68 (2006.01) INTELLECUTAL PROPERTY DEPARTMENT C7H 2L/04 (2006.01) 32O WAKARAWAY CI2M 3/00 (2006.01) SALT LAKE CITY, UT 84108 (US) (52) U.S. Cl...... 435/6; 536/23.2; 435/287.2: 257/E51; 977/924 (73) Assignee: Myriad Genetics, Incorporated, Salt Lake City, UT (US) (57) ABSTRACT (21) Appl. No.: 11/450,909 Variants in TLK1, WARS2, ARTS2, MSR, AKAP9, DNAJD1, GOLPH4, RABEP1, TAP2, NARG2, DDX58, (22) Filed: Jun. 8, 2006 CD39, FKBP1a, SRI, XRRA1, IRF5 and AMFR are disclosed which are useful as biomarkers for predicting the Related U.S. Application Data TLK1, WARS2, ARTS2, MSR, AKAP9, DNAJD1, GOLPH4, RABEP1, TAP2, NARG2, DDX58, CD39, (60) Provisional application No. 60/688,459, filed on Jun. FKBP1a, SRI, XRRA1, IRF5 or AMFR gene expression 8, 2005. Provisional application No. 60/688,592, filed level and the biological functions associated thereof. Patent Application Publication Apr. 12, 2007 Sheet 1 of 9 US 2007/0082347 A1

EX7(a+190 C/C T/C T/T TLK1 Transcript expression level Figure 1

S

EX6(a)2152 G/G G/A A/A WARS2 Transcript Expression Level Figure 2 Patent Application Publication Apr. 12, 2007 Sheet 2 of 9 US 2007/0082347 A1

EX19Q885 C/C C/T T/T ARTS Transcript Expression Level Figure 3

Ex7G146 A/G A/A MSR Transcript expression level Fi gure 4 Patent Application Publication Apr. 12, 2007 Sheet 3 of 9 US 2007/0082347 A1

5 6 7 8

EX10G186 G/G A/G A/A AKAP9 Transcript Expression Level Figure 5 /\ f |

EX1(a)368 T/T C/T C/C DNAJD1 Transcript Expression Level

Figure 6 Patent Application Publication Apr. 12, 2007 Sheet 4 of 9 US 2007/0082347 A1

5 6 7 8 9 EX15G-85 G/G C/G GOLPH4 Transcript expression level Figure 7

EX17(a)15 A/A A/G G/G RABEP1 Transcript Expression Levels

Figure 8 Patent Application Publication Apr. 12, 2007 Sheet 5 of 9 US 2007/0082347 A1

EX12G61 A/A AVG G/G TAP2 Transcript Expression Level Figure 9

S 5.5 S S.5 7 75 8 EX12648 C/C T/C T/T NARG2 Transcript Expression Level Figure 10 Patent Application Publication Apr. 12, 2007 Sheet 6 of 9 US 2007/0082347 A1

EX14(a)+78 C/C C/T T/T DDX58 Transcript Expression Level Figure 11

9.5 1O 10.5 11 11.5 6 Position 97,374,982 G/G A/G AWA CD39 Transcript Expression Level

Figure 12 Patent Application Publication Apr. 12, 2007 Sheet 7 of 9 US 2007/0082347 A1

EX5(a).8 G/G A/G A/A FKBP1 a Transcript Expression Level Figure 13 VX

SRI Transcript Expression Level

Figure 14 Patent Application Publication Apr. 12, 2007 Sheet 8 of 9 US 2007/0082347 A1

5.5 S S5 7 7.5 EX2Q26 C/C C/G G/G XRRA1 Transcript Expression Level Figure 15

EX9Q80 A/A G/A G/G IRF5 Transcript Expression Level Figure 16 Patent Application Publication Apr. 12, 2007 Sheet 9 of 9 US 2007/0082347 A1

5 6 7 B 9 10 11 EX14(a483 G/G G/A AA AMFR Transcript expression level

Figure 17 US 2007/0O82347 A1 Apr. 12, 2007

GENEVARIANTS AND USE THEREOF 18:505-508 (2000): Nebert, Am. J. Hum. Genet. 60:265-271 (1997); and Puga et al., Crit. Rev. Toxicol. 27(2):199-222 CROSS-REFERENCE TO RELATED (1997). Pharmacogenomic studies have found a large num APPLICATIONS ber of SNPs associated with differing drug response. For example, genetic polymorphic variations in the 5-lipoxyge 0001. This application claims priority under 35 U.S.C. S nase gene, which codes for an anti-asthma drug target, have 119(e) to U.S. provisional application Ser. No. 60/698.211, been linked to variations in drug response. See DraZen et al., filed Jul. 11, 2005: U.S. provisional application Ser. No. Nat. Genet. 22:168-170 (1999). In addition, genetic variants 60/741,350, filed Nov. 30, 2005: U.S. provisional applica in the drug-metabolizing enzyme thiopurine methyltrans tion Ser. No. 60/688,592, filed Jun. 8, 2005: U.S. provisional application Ser. No. 60/741,274, filed Nov. 30, 2005: U.S. ferase correlate with adverse drug reactions. See Krynetski provisional application Ser. No. 60/688,459, filed Jun. 8, et al., Pharm. Res., 16:342-349 (1999). 2005: U.S. provisional application Ser. No. 60/741,173, filed 0006 Since are intimately involved in essential Nov.30, 2005: U.S. provisional application Ser. No. 60/741, biological functions and drug metabolism, the apparent 351, filed Nov. 30, 2005; and U.S. provisional application nexus between genetic polymorphic variations and human Ser. No. 60/698,179, filed Jul. 11, 2005, all of which are diseases and drug responses is not at all Surprising since any hereby incorporated by reference in their entirety. gene sequence change may potentially affect gene expres sion and function. For example, SNPs in exons may REFERENCE TO A “SEQUENCE LISTING." A lead to different protein sequences exhibiting altered protein TABLE, OR A COMPUTER PROGRAM LISTING activities (e.g., sickle cell anemia). SNPs in exons, and thus APPENDIX SUBMITTED ON A COMPACT mRNAS, may also affect the splicing, processing, transport, DISC translation, or stability of the mRNAs that contain them. See e.g., Cooper et al., in The Metabolic and Molecular Bases of 0002 A Sequence Listing containing all relevant nucle Inherited Diseases, 1:259-291 (1995), Scriver et al., eds., otide and/or amino acid sequences has been Submitted on 3 McGraw-Hill, New York. SNPs in exons may also alter compact discs (CDs). The CD labeled “CRF contains one mRNA secondary or tertiary structures, i.e., mRNA folding, file entitled “3107-01-1U 2006-06-08 SEQ-LIST-TXT.” and thus affect post-transcriptional gene regulation. See Tables 1-81 are also contained in the accompanying CDs, labeled “Copy 1 and “Copy 2,” each containing two files Shen et al., Proc. Natl. Acad. Sci. USA, 96:7871-7876 entitled “3107-01-1U 2006-06-08 SEQ-LIST TXT and (1999). 31 O7-01-1U 2006-06-08 Tables TH. The file 31 O7-01-1U 0007 Polymorphic variations in non-coding regions have 2006-06-08 SEQ-LIST TXT was created and written onto also been linked to diseases and other phenotypic effects. CD on Jun. 8, 2006, and is 854 kilobytes in size. The file For example, SNPs in introns can affect mRNA splicing and “3107-01-1U 2006-06-08 Tables TH' was created and writ thus alter gene expression. See e.g., Otterness et al., J. Clin. ten onto CD on Jun. 8, 2006, and is 2.1 megabytes in size. Invest., 101(5):1036-44 (1998); Hayashi et al., Growth The information contained on these CDs is hereby incorpo Horm. IGF Res., 9:434–437 (1999); Tsai et al., Biochem. rated by reference in its entirety. Mol. Med., 61:9-15 (1997); Yu et al., Atherosclerosis, 146:125-31 (1999); Nemer et al., Blood, 89:4608-16 (1997); FIELD OF THE INVENTION States et al., Mutat. Res., 363:171-7 (1996). Genetic varia tions in intronic sequences may also influence gene tran 0003. This invention generally relates to pharmacogenet Scription or interactions between gene transcription products ics, particularly to the identification of genetic variants that and other cellular machines. Likewise, polymorphic varia are associated with gene expression, and methods of using tions in transcriptional regulatory regions of a gene may the identified variants. alter transcriptional patterns of the gene. See McGuigan et al., Osteoporos. Int., 11:338-43 (2000); Arnaud et al., Arte BACKGROUND OF THE INVENTION rioscler. Thromb. Vasc. Biol., 20:892-898 (2000). 0004 Genetic polymorphic variations such as single 0008 Very often, a genetic polymorphic variant alone nucleotide polymorphisms (SNPs) are valuable tools for does not cause any detectable effect on gene expression or deciphering mechanisms of biological functions and under gene function. However, it may act in concert with other standing the underlying basis of human diseases. See gen known or unknown polymorphic variants in the gene and erally, Cooper et al. in The Metabolic and Molecular Bases cause cumulative or synergistic effect Sufficient to alter gene of Inherited Diseases, 1:259-291 (1995), Scriver et al., eds., expression pattern or the properties of the protein encoded McGraw-Hill, New York. SNPs are small variations in by the gene. Even if a particular genetic polymorphic variant genomes. They are among the most common forms of does not contribute to any changes in gene expression or human genetic variations. A large number of monogenic protein function, it may be near or linked to one or more human diseases are associated with genetic polymorphic other genetic variants that directly cause phenotypic defects. variations such as SNPs in the so-called susceptibility genes. Therefore, by identifying such genetic variants, one could For example, polymorphic variations in the coagulation reasonably predict the phenotypic effect in an individual factor gene F5 have been linked directly to deep-vein having Such genetic variants. In addition, one can also thrombosis. See Bertina et al., Nature, 369:64-67 (1994). identify haplotypes, that is, combinations of genetic variants SNPs in the Apollipoprotein E gene correlate with the risk of in a particular gene or chromosome present in an individual. Alzheimer's disease. See U.S. Pat. No. 5,773,220. Haplotypes represent patterns of genetic variations and are 0005 Genetic polymorphic variations are also associated important tools for genetic analysis and diagnosis. with varying response to drugs and natural environmental 0009 Indeed, genetic polymorphic variations such as agents. See generally, McCarthy et al., Nat. Biotechnol., SNPs and haplotypes containing SNPs are invaluable US 2007/0O82347 A1 Apr. 12, 2007 genetic markers for a variety of applications. For example, 0014) Dysregulation of WARS2 expression has been genetic polymorphic variations are useful in genetic analysis associated with diseases Such as cancer, neurodegenerative for studying polymorphic allele segregation and polymor and cardiovascular disease. Thus, SNPs and haplotypes of phism origins. In addition, genetic polymorphisms can be the present invention in TLK1, of the present invention are used as markers in population studies, and in forensic useful as biomarkers for the prediction and detection of such medicine. More importantly, SNPs can be particularly useful diseases, and for determining cancer prognosis in a patient. in genetic diagnoses for identifying individuals predisposed 0.015 ARTS1 expression levels have been linked to to certain diseases. See e.g., U.S. Pat. Nos. 5,994,080, tumor Suppression, blood pressure regulation, immune 5,942,390, 5,773,220, and 5,736,323. Further, SNPs can also response and autoimmune disease. Thus, SNPs associated be valuable tools for predicting an individual’s response to with alterations in ARTS1 mRNA expression levels are drug treatment or other exogenous interventions. useful as biomarkers to predict or detect susceptibility to 0010 Thus, there is need in the art to identify additional Such diseases in patients, and to predict patient response to SNPs in the , particularly those associated the treatment of Such diseases. with defined phenotypes. 0016 MSR is a critical enzyme in methionine metabo lism, reducing methionine synthetase cofactor cobalamin to SUMMARY OF THE INVENTION its active state. As such, MSR levels are central to efficient 0011. The present invention is based on the discovery of methionine metabolism. Methionine is also necessary for a number of genetic polymorphic variations, particularly cancer cell proliferation in vitro. Accordingly, altering levels SNPs and haplotypes, in the human autocrine motility factor of MSR affects the level of methionine thereby altering the receptor gene (“AMFR), human tousled-like kinase 1 gene rate of cancer cell growth. Thus, the SNPs and haplotypes of (“TLK1), human mitochondrial tryptophanyl-tRNA syn the present invention, which are associated with MSR thetase gene (“WARS2), human adipocyte-derived leucine mRNA expression levels, are useful as biomarkers for aminopeptidase gene (“ARTS2), human methionine Syn diseases such as atherosclerosis, thrombosis, methylmaloni thase reductase gene (“MSR), human A-kinase anchor caciduria and cancer. protein 9 gene ( AKAP9), human Homosapiens DnaJ 0017 AKAP9 expression has been linked to neurodegen (Hsp40) homolog, subfamily D, member 1 gene erative disorders, cardiovascular disease, cancer and depres (“DNAJD1), human golgi phosphoprotein gene sion in humans. The SNPs of the present invention associ (“GOLPH4), human RAB GTPase binding effector protein ated with altered levels of AKAP9 mRNA expression are 1 gene (“RABEP1), human transporter associated with therefore useful to predict or detect susceptibility to neuro antigen processing gene (“TAP2), human NMDA receptor degenerative disorders, cardiovascular disease, cancer and regulated gene 2 gene (“NARG2), human DEAD-box depression. polypeptide 58 gene (“DDX58), human CD39 antigen gene (“CD39), human FK506-binding protein 1a gene 0018 DNAJD1 expression levels have been associated (“FKBP1a), human sorcin gene (“SRI), human X-ray with resistance to chemotherapeutics in ovarian cancer, and resistance associated protein gene (XRRA1), human inter polymorphisms predicting DNAJD1 levels have utility as feron regulatory factor gene (“IRF) and human autocrine predictive markers for therapeutic responses to apoptosis motility factor receptor gene (“AMFR). The SNPs and/or inducing agents in cancer therapy. Thus, the SNPs of the haplotypes are summarized in Tables 1-35. It has also been present invention in the DNAJD1 gene, which are associated surprisingly discovered that the mRNA expression levels of with altered DNAJD1 expression levels, are useful biomar these genes are inherited in a Mendelian manner in humans. kers for predicting the effectiveness of cancer treatments in Furthermore, the SNPs and/or haplotypes are associated patients. with the heritable mRNA levels of the gene transcripts. 0019. Under-expression of GOLPH4 results in protein Thus, the SNPs and haplotypes are useful in predicting accumulation in early/recycling endoSomes of those proteins mRNA levels of the genes in human cells and tissues, and that use the bypass pathway. Under-expression of GOLPH4 thus can be useful in predicting the gene expression and the also inhibits invasion of cells by toxins. Therefore, GOLPH4 biological functions associated therewith. plays an important role in the movement of proteins and 0012 For example, over-expression of AMFR induces a toxins from endoSomes to the Golgi apparatus via the bypass transformed phenotype and produces tumors in nude mice. pathway. Thus, the SNPs of the present invention in the Also, expression levels of AMFR in tumor cells correlate GOLPH4 gene, which are associated with altered GOLPH4 with the cells' potential to metastasize. Thus, the SNPs and expression levels, are useful biomarkers for determining the haplotypes of the present invention in AMFR, which are Susceptibility of patients to toxins and pathogen invasion. associated with inheritable AMFR mRNA expression levels, 0020 RABEP1 levels have been shown to influence are useful biomarkers for the prognosis of cancer in patients. endosomal trafficking associated with neurodegenerative diseases. Altered RABEP1 expression has also been asso 0013 In addition, TLK1 overexpression increases resis ciated with tumor formation and growth. Thus, SNPs asso tance to DNA damage caused by ionizing radiation. Expres ciated with altered RABEP1 mRNA levels are useful as sion of a dominant-negative kinase TLK1 mutant results in biomarkers to predict and detect Susceptibility to cancer and chromosome missegregation and aneuploidy, indicating the neurodegenerative disease in an individual, as well as to role of TLK1 in preserving genetic integrity. Thus, the SNPs predict tumor progression. and haplotypes of the present invention in TLK1, which are associated with inheritable TLK1 mRNA expression levels, 0021 TAP2 mRNA expression levels correlate with are useful biomarkers for the prediction of response to expression of cell Surface proteins involved in autoimmune radiation treatment in patients. function, immune response and cancer cell metastasis. Thus, US 2007/0O82347 A1 Apr. 12, 2007

SNPs associated with altered TAP2 mRNA expression levels DNAJD1, GOLPH4, RABEP1, TAP2, NARG2, DDX58, are useful in the prediction and detection of susceptibility to CD39, FKBP1a, SRI, XRRA1, IRF5 and AMFR nucleic autoimmune disease, viral infection and cancer development acid variant is provided containing at least one of the newly in an individual. The SNPs are also useful in determining the discovered genetic variants, as Summarized in Tables 1-35. potential for progression of viral infection and cancer cell The present invention also encompasses an isolated oligo metastasis. nucleotide comprising a contiguous span of at least 18, 0022 NARG2 expression levels increase in the absence preferably from 18 to 50 nucleotides of the sequence of one of NMDA receptor 1 demonstrating the influence of NARG2 of the above nucleic acid variants, wherein the contiguous level on neuronal cell differentiation. Thus, the SNPs of the span encompasses and contains a nucleotide variant selected present invention showing an association with NARG2 from those in Tables 1-35. mRNA expression levels are useful as a means of predicting/ 0030 DNA microchips are also provided comprising one detecting Susceptibility and/or progression of neurological or more isolated nucleic acid variants and/or one or more disease in an individual. isolated oligonucleotides according to the present invention. 0023 DDX58 levels correlate with COX2 levels, which 0031. In accordance with another aspect of the invention, have been shown to have an association with cancer, mainly an isolated TLK1, WARS2, ARTS2, MSR, AKAP9, tumor formation and growth. DDX58 expression levels are DNAJD1, GOLPH4, RABEP1, TAP2, NARG2, DDX58, also associated with the activity of natural killer cells and CD39, FKBP1a, SRI, XRRA1, IRF5 and AMFR protein cytotoxicity in response to viral infection. Thus, SNPs variant, or a fragment thereof, is provided comprising one or associated with DDX58 mRNA levels are useful as biom more amino acid variants selected from those in Tables 1-35. arkers to predict and detect Susceptibility to cancer and viral 0032. The present invention also provides an isolated infection. antibody specifically immunoreactive with a protein variant 0024. CD39 levels correlate with susceptibility to vascu of the present invention. lar injury and coronary syndromes. CD39 expression levels 0033. In accordance with yet another aspect of the are also associated with rates of hemostasis and thromobo present invention, a method is provided for genotyping an sis. Further, levels of CD39 have been associated with the individual by determining whether the individual has a inflammatory response. Thus, SNPs associated with CD39 nucleotide variant or an amino acid variant provided in mRNA levels are useful as biomarkers to predict and detect accordance with the present invention. In addition, the Susceptibility to vascular injury, coronary disease, transplant present invention also provides a method for predicting in an rejection and inflammatory response. individual the gene expression level or mRNA level of the 0025 FKBP1a levels correlate with susceptibility to vas TLK1, WARS2, ARTS2, MSR, AKAP9, DNAJD1, cular injury and coronary syndromes. FKBP1a expression GOLPH4, RABEP1, TAP2, NARG2, DDX58, CD39, levels are also associated with rates of hemostasis and FKBP1a, SRI, XRRA1, IRF5 and AMFR genes. The method thromobosis. Further, levels of FKBP1a have been associ comprises the step of detecting in the individual the presence ated with the inflammatory response. Thus, SNPs associated or absence of a nucleotide variant, or an amino acid variant, with FKBP1 a mRNA levels are useful as biomarkers to provided according to the present invention, which is asso predict and detect Susceptibility to vascular injury, coronary ciated with an inheritable mRNA expression level. disease, transplant rejection and inflammatory response. 0034. In accordance with another aspect of the invention, 0026 Expression levels of SRI have been associated with a detection kit is also provided for genotyping the nucleotide the prognosis and remission rate of acute myeloid lym variant in an individual. In a specific embodiment, the kit is phoma cancer. SRI expression levels are also associated used in predicting the level of gene expression in an indi with resistance to chemotherapeutics in vitro and in vivo. vidual. The kit may include, in a carrier or confined com The expression of SRI has also been shown to be associated partment, any nucleic acid probes or primers, or antibodies with increased cardiac contractility and recovery of cardi useful for detecting the nucleotide variants or amino acid omyopathy. Thus, SNP associated with SRI mRNA levels variants of the present invention as described herein. The kit are useful as biomarkers to predict prognosis and remission can also include other reagents such as DNA polymerase, rates of cancer as well as patient response to treatment with buffers, nucleotides and others that can be used in the chemotherapeutics. The SRI SNP of the present invention is method of detecting the variants according to this invention. also useful as a biomarker in detecting ability to recover In addition, the kit preferably also contains instructions for from cardiovascular disease. its use. 0035. The foregoing and other advantages and features of 0027 XRRA1 levels correlate with cell sensitivity to the invention, and the manner in which the same are ionizing radiation. Thus, SNPs associated with XRRA1 accomplished, will become more readily apparent upon mRNA expression levels are useful as biomarkers to predict consideration of the following detailed description of the and detect sensitivity to ionizing radiation. invention taken in conjunction with the accompanying 0028 IRF5 mRNA expression levels have been associ examples and drawings, which illustrate preferred and ated with immune response to viral infection in humans. exemplary embodiments. Thus, SNPs of the present invention are useful as biomarkers to predict and detect Susceptibility to and progression of BRIEF DESCRIPTION OF THE DRAWINGS viral infection in an individual. 0.036 FIGS. 1-17 show the relative mRNA expression 0029. Accordingly, in a first aspect of the present inven levels of the variant genotypes for particular SNPs in the tion, an isolated TLK1, WARS2, ARTS2, MSR, AKAP9, TLK1, WARS2, ARTS2, MSR, AKAP9, DNAJD1, US 2007/0O82347 A1 Apr. 12, 2007

GOLPH4, RABEP1, TAP2, NARG2, DDX58, CD39, level. The figure shows the relative expression levels of the FKBP1a, SRI, XRRA1, IRF5 and AMFR genes. The relative genotypes G/G, A/G and A/A; expression is based on signal intensities from the RNA expression chips in a logarithmic fashion. For instance, a 0050 FIG. 14 is a plot illustrating the association of the difference of one unit represents a two-fold difference in SRI genotype at EX9(a)351 with the SRI mRNA level. The mRNA expression levels, whereas a difference of three figure shows the relative expression levels of the genotypes represents an eight-fold increase in expression; C/C, C/T and T/T: 0037 FIG. 1 is a plot illustrating the association of the 0051 FIG. 15 is a plot illustrating the association of the TLK1 genotype at EX7(a)--190 with the TLK1 mRNA level. XRRA1 genotype at EX2(a)26 with the XRRA1 mRNA The figure shows the relative expression levels of the level. The figure shows the relative expression levels of the different genotypes C/C, T/C and T/T: different genotypes C/C, C/G and G/G: 0038 FIG. 2 is a plot illustrating the association of the 0052 FIG. 16 is a plot illustrating the association of the WARS2 genotype at EX6(a)2152 with the WARS2 mRNA IRF5 genotype at EX19(a)9328 with the IRF5 mRNA level. level. The figure shows the relative expression levels of the The figure shows the relative expression levels of the different genotypes G/G, A/G and A/A; genotypes A/A, A/G and G/G; and 0.039 FIG. 3 is a plot illustrating the association of the 0053 FIG. 17 is a plot illustrating the association of the ARTS1 genotype at EX19(a)328 with the ARTS1 mRNA AMFR genotype at EX14(a)483 with the AMFR mRNA level. The figure shows the relative expression levels of the level. The figure shows the relative expression levels of the different genotypes C/C, C/T and T/T: genotypes G/G, G/A and A/A. 0040 FIG. 4 is a plot illustrating the association of the DETAILED DESCRIPTION OF THE MSR genotype at EX7(a)146 with the MSR mRNA level. INVENTION The figure shows the relative expression levels of the different genotypes A/G and A/A; 1. Definitions 0041 FIG. 5 is a plot illustrating the association of the 0054 The terms “genetic variant' and “nucleotide vari AKAP9 genotype at EX10(a)186 with the AKAP9 mRNA ant” are used herein interchangeably to refer to changes or level. The figure shows the relative expression levels of the alterations to, or variations in, the reference human TLK1. different genotypes G/G, A/G and A/A; WARS2, ARTS2, MSR, AKAP9, DNAJD1, GOLPH4, RABEP1, TAP2, NARG2, DDX58, CD39, FKBP1a, SRI, 0.042 FIG. 6 is a plot illustrating the association of the XRRA1, IRF5 and AMFR gene or cDNA sequence at a DNAJD1 genotype at EX1(a)368 with the corresponding particular , including, but not limited to, nucleotide DNAJD1 mRNA level. The figure shows the relative expres base deletions, insertions, inversions, and Substitutions in sion levels of the different genotypes T/T, T/C and C/C: the coding and noncoding regions. Deletions may be of a 0.043 FIG. 7 is a plot illustrating the association of the single nucleotide base, a portion or a region of the nucleotide GOLPH4 genotype at EX15(a)-85 with the GOLPH4 sequence of the gene, or of the entire gene sequence. mRNA level. The figure shows the relative expression levels Insertions may be of one or more nucleotide bases. The of the genotypes G/G and C/G; “genetic variant' or “nucleotide variant may occur in transcriptional regulatory regions, untranslated regions of 0044 FIG. 8 is a plot illustrating the association of the mRNA, exons, introns, or exon/intron junctions. The RABEP1 genotype at EX17(a)15 with the RABEP1 mRNA “genetic variant' or “nucleotide variant may or may not level. The figure shows the relative expression levels of the result in stop codons, frame shifts, deletions of amino acids, genotypes A/A, A/G and G/G; altered gene transcript splice forms or altered amino acid 0045 FIG. 9 is a plot illustrating the association of the Sequence. TAP2 genotype at EX12(a)61 with the TAP2 mRNA level. 0055. The term “allele" or “gene allele" is used herein to The figure shows the relative expression levels of the refer generally to a naturally occurring gene having a genotypes A/A, A/G and G/G; reference sequence or a gene containing a specific nucle 0046 FIG. 10 is a plot illustrating the association of the otide variant. NARG2 genotype at EX12(a)48 with the NARG2 mRNA 0056. As used herein, “haplotype' is a combination of level. The figure shows the relative expression levels of the genetic (nucleotide) variants in a region of an mRNA or a genotypes C/C, C/T and T/T: genomic DNA on a chromosome found in an individual. 0047 FIG. 11 is a plot illustrating the association of the Thus, a haplotype includes a number of genetically linked DDX58 genotype at EX14(a)+78 with the DDX58 mRNA polymorphic variants that are typically inherited together as level. The figure shows the relative expression levels of the a unit. genotypes C/C, C/T and T/T: 0057. As used herein, the term "amino acid variant is 0.048 FIG. 12 is a plot illustrating the association of the used to refer to an amino acid change to, or an amino acid CD39 genotype at 97,374,982 with the CD39 mRNA level. variant of, a reference human TLK1, WARS2, ARTS2, The figure shows the relative expression levels of the MSR, AKAP9, DNAJD1, GOLPH4, RABEP1, TAP2, NARG2, DDX58, CD39, FKBP1a, SRI, XRRA1, IRF5 or different genotypes G/G, A/G and A/A; AMFR amino acid sequence resulting from a "genetic 0049 FIG. 13 is a plot illustrating the association of the variant' or “nucleotide variant' of the human gene encoding CD39 genotype at 97,374,982 with the FKBP1a mRNA TLK1, WARS2, ARTS2, MSR, AKAP9, DNAJD1, US 2007/0O82347 A1 Apr. 12, 2007

GOLPH4, RABEP1, TAP2, NARG2, DDX58, CD39, chromosome but not one or more other portions present on FKBP1a, SRI, XRRA1, IRF5 or AMFR. The term “amino the same chromosome. More specifically, an "isolated acid variant' is intended to encompass not only single amino nucleic acid' typically includes no more than 25 kb naturally acid Substitutions, but also amino acid deletions, insertions, occurring nucleic acid sequences which immediately flank and other significant changes of amino acid sequence in the nucleic acid in the naturally existing chromosome (or a TLK1, WARS2, ARTS2, MSR, AKAP9, DNAJD1, viral equivalent thereof). However, it is noted that an “iso GOLPH4, RABEP1, TAP2, NARG2, DDX58, CD39, lated nucleic acid as used herein is distinct from a clone in FKBP1a, SRI, XRRA1, IRF5 or AMFR. a conventional library such as genomic DNA library and cDNA library in that the clone in a library is still in 0.058. The term “genotype' as used herein means the admixture with almost all the other nucleic acids of a nucleotide characters at a particular nucleotide variant chromosome or cell. Thus, an "isolated nucleic acid as used marker (or locus) in either one allele or both alleles of a gene herein also should be substantially separated from other (or a particular intergenic chromosome region). With respect naturally occurring nucleic acids that are on a different to a particular nucleotide position of a gene of interest, the chromosome of the same organism. Specifically, an “iso nucleotide(s) at that locus or equivalent thereof in one or lated nucleic acid' means a composition in which the both alleles form the genotype of the gene at that locus. A specified nucleic acid molecule is significantly enriched so genotype can be homozygous, heterozygous or hemizygous. as to constitute at least 10% of the total nucleic acids in the Accordingly, “genotyping” means determining the geno composition. type, that is, the nucleotide(s) at a particular chromosome locus. Genotyping can also be done by determining the 0063 An "isolated nucleic acid can be a hybrid nucleic amino acid variant at a particular position of a protein which acid having the specified nucleic acid molecule covalently can be used to deduce the corresponding nucleotide vari linked to one or more nucleic acid molecules that are not the ant(s). nucleic acids naturally flanking the specified nucleic acid. 0059) The term “locus” refers to a specific position or site For example, an isolated nucleic acid can be in a vector. In in a gene sequence, chromosome, or protein. Thus, there addition, the specified nucleic acid may have a nucleotide may be one or more contiguous nucleotides in a particular sequence that is identical to a naturally occurring nucleic gene or chromosomal locus, or one or more amino acids at acid or a modified form or mutein thereof having one or a particular locus in a polypeptide. Moreover, "locus' may more mutations such as nucleotide Substitution, deletion, also be used to refer to a particular position in a gene or insertion, inversion, and the like. chromosome where one or more nucleotides have been 0064. An isolated nucleic acid can be prepared from a deleted, inserted, or inverted. recombinant host cell (in which the nucleic acids have been 0060. As used herein, the terms “polypeptide.'"protein.” recombinantly amplified and/or expressed), or can be a and "peptide' are used interchangeably to refer to an amino chemically synthesized nucleic acid having a naturally acid chain in which the amino acid residues are linked by occurring nucleotide sequence or an artificially modified covalent peptide bonds. The amino acid chain can be of any form thereof. length of at least two amino acids, including full-length 0065. The term "isolated polypeptide' as used herein is proteins. Unless otherwise specified, the terms “polypeptide, defined as a polypeptide molecule that is present in a form '"protein, and “peptide' also encompass various modified other than that found in nature. Thus, an isolated polypeptide forms thereof, including but not limited to glycosylated can be a non-naturally occurring polypeptide. For example, forms, phosphorylated forms, etc. an "isolated polypeptide' can be a “hybrid polypeptide. An 0061 The terms “primer”, “probe,” and "oligonucle "isolated polypeptide' can also be a polypeptide derived otide' are used herein interchangeably to refer to a relatively from a naturally occurring polypeptide by additions or short nucleic acid fragment or sequence. They can be DNA, deletions or Substitutions of amino acids. An isolated RNA, or a hybrid thereof, or chemically modified analogs or polypeptide can also be a “purified polypeptide' which is derivatives thereof. Typically, they are single-stranded. used herein to mean a composition or preparation in which However, they can also be double-stranded having two the specified polypeptide molecule is significantly enriched complementing Strands that can be separated by denatur so as to constitute at least 10% of the total protein content ation. Normally, they have a length of from about 8 nucle in the composition. A “purified polypeptide' can be obtained otides to about 200 nucleotides, preferably from about 12 from natural or recombinant host cells by standard purifi nucleotides to about 100 nucleotides, and more preferably cation techniques, or by chemically synthesis, as will be about 18 to about 50 nucleotides. They can be labeled with apparent to skilled artisans. detectable markers or modified in any conventional manners 0.066. The terms “hybrid protein,”“hybrid polypeptide, for various molecular biological applications. “hybrid peptide,”“fusion protein,”“fusion polypeptide.” 0062) The term “isolated” when used in reference to and “fusion peptide' are used herein interchangeably to nucleic acids (e.g., genomic DNAS, cDNAS, mRNAS, or mean a non-naturally occurring polypeptide or isolated fragments thereof) is intended to mean that a nucleic acid polypeptide having a specified polypeptide molecule molecule is present in a form that is Substantially separated covalently linked to one or more other polypeptide mol from other naturally occurring nucleic acids that are nor ecules that do not link to the specified polypeptide in nature. mally associated with the molecule. Specifically, since a Thus, a “hybrid protein’ may be two naturally occurring naturally existing chromosome (or a viral equivalent proteins or fragments thereof linked together by a covalent thereof) includes a long nucleic acid sequence, an "isolated linkage. A “hybrid protein’ may also be a protein formed by nucleic acid as used herein means a nucleic acid molecule covalently linking two artificial polypeptides together. Typi having only a portion of the nucleic acid sequence in the cally but not necessarily, the two or more polypeptide US 2007/0O82347 A1 Apr. 12, 2007 molecules are linked or “fused together by a peptide bond 0069. As used herein the term “linkage disequilibrium.” forming a single non-branched polypeptide chain. or “LD,” means that there is interdependence between alleles at loci closely positioned within a genome. More 0067. The term “high stringency hybridization condi precisely, LD means that the probability to find allele A at tions,” when used in connection with nucleic acid hybrid locus 1 depends on whether allele B is present at locus 2. ization, means hybridization conducted overnight at 42°C. Complete LD means that alleles A and B are always found in a solution containing 50% formamide, 5xSSC (750 mM together. Pitchard and Przeworski, Am. J. Hum. Genet., NaCl, 75 mM sodium citrate), 50 mM sodium phosphate, pH 69:1-4 (2001) teaches a widely used measure of LD: 7.6, 5x Denhardt’s solution, 10% dextran sulfate, and 20 microgram/ml denatured and sheared salmon sperm DNA, with hybridization filters washed in 0.1xSSC at about 65° C. 0070 where A and a are two alleles at locus 1, B and b The term “moderate stringent hybridization conditions.” are two alleles at locus 2, and PCX) is the probability of X when used in connection with nucleic acid hybridization, 0.071) If LD is absent, then P(AB)=P(A)P(B), and, there means hybridization conducted overnight at 37° C. in a fore, r=0. In contrast, in the case of complete disequilib solution containing 50% formamide, 5xSSC (750 mM NaCl, rium, P(AB)=P(A)=P(B), and, therefore, r=1. In the case of 75 mM sodium citrate), 50 mM sodium phosphate, pH 7.6, partial LD, r is between 0 and 1, and high values of r 5x Denhardt's solution, 10% dextran sulfate, and 20 micro correspond to strong LD. If allele A of locus 1 is associated gram/ml denatured and sheared salmon sperm DNA, with with a disease, and there is a strong LD between locus 1 and hybridization filters washed in 1xSSC at about 50° C. It is locus 2, so that P(AB)>P(A)P(B), then allele B is associated noted that many other hybridization methods, Solutions and with the disease too. To define strong LD, a threshold of temperatures can be used to achieve comparable stringent r>0.8 is usually used. See Carlson et al, Nat. Genet., hybridization conditions as will be apparent to skilled arti 33(4):518-21 (2003). This threshold has been applied in SaS. identifying additional SNPs that are in LD with the disease, 0068 For the purpose of comparing two different nucleic disorder or phenotype-associated SNP of the instant inven acid or polypeptide sequences, one sequence (test sequence) tion. may be described to be a specific "percentage identical to 0072 Thus, when a second nucleotide variant is said another sequence (comparison or reference sequence) in the herein to be in linkage disequilibrium, or LD, with a first present disclosure. In this respect, the percentage identity is nucleotide variant, it is meant that a second variant is closely determined by the algorithm of Karlin and Altschul, Proc. dependent upon a first variant, with a r value of at least 0.8, Natl. Acad. Sci. USA, 90:5873-5877 (1993), which is incor as calculated by the formula above. Thus, the term “LD porated into various BLAST programs. Specifically, the variants' as used herein means variants that are in linkage percentage identity is determined by the “BLAST 2 disequilibrium with an r value of at least 0.8. Sequences” tool, which is available through the National Center for Biotechnology Informations (NCBI's) website. 0073. The term “reference sequence” refers to a poly See Tatusova and Madden, FEMS Microbiol. Lett., nucleotide or polypeptide sequence known in the art, includ 174(2):247-250 (1999). For pairwise DNA-DNA compari ing those disclosed in publicly accessible databases, e.g., son, the BLASTN 2.1.2 program is used with default param or GenBank, or a newly identified gene sequence, eters (Match: 1; Mismatch: -2; Open gap: 5 penalties: used simply as a reference with respect to the nucleotide extension gap: 2 penalties; gap X dropoff 50, expect: 10; variants provided in the present invention. The nucleotide or and word size: 11, with filter). For pairwise protein-protein amino acid sequence in a reference sequence is contrasted to sequence comparison, the BLASTP 2.1.2 program is the alleles disclosed in the present invention having newly employed using default parameters (Matrix: BLOSUM62; discovered nucleotide or amino acid variants. In the instant gap open: 11, gap extension: 1; X dropoff. 15; expect: 10.0; disclosure, for TLK1 genomic DNA, the sequence provided and wordsize: 3, with filter). Percent identity of two by GenBank Accession No. AC007739 (PRI 7-Oct.-2000) or sequences is calculated by aligning a test sequence with a AC009953 (PRI 30-Sep-2000) or AC010092 (PRI 08-Nov.- comparison sequence using BLAST 2.1.2, determining the 2000) is used as a reference sequence, while the nucleotide number of amino acids or nucleotides in the aligned test and amino acid sequences provided by GenBank Accession sequence that are identical to amino acids or nucleotides in No. AB004885 (PRI 5-Feb-1999) (see SEQ ID NOs: 1 and the same position of the comparison sequence, and dividing 2) are used as the reference sequences for TLK1 clNA and the number of identical amino acids or nucleotides by the protein, respectively. number of amino acids or nucleotides in the comparison 0074 For WARS2 genomic DNA, the sequence provided sequence. When BLAST 2.1.2 is used to compare two sequences, it aligns the sequences and yields the percent by GenBank Accession No. AL139420 (PRI 18-May-2005), identity over defined, aligned regions. If the two sequences AL359823 (PRI 19-May-2005) and AL590288 (PRI are aligned across their entire length, the percent identity 18-May-2005) are used as a reference sequence, while the yielded by the BLAST 2.1.1 is the percent identity of the two nucleotide and amino acid sequences provided by GenBank sequences. If BLAST 2.1.2 does not align the two sequences Accession No. NM 015836 (PRI 23-Apr-2005) (see SEQ over their entire length, then the number of identical amino ID NO:18 and 19) and NM 201263 (PRI 5-Jun-2005) (see acids or nucleotides in the unaligned regions of the test SEQID NOS:20 and 21) are used as the reference sequences sequence and comparison sequence is considered to be Zero for WARS2 cDNA and protein, respectively. and the percent identity is calculated by adding the number 0075) For ARTS2 genomic DNA, the sequence provided of identical amino acids or nucleotides in the aligned regions by GenBank Accession No. AC009073 (PRI 5-Jul-2000) is and dividing that number by the length of the comparison used as a reference sequence, while the nucleotide and Sequence. amino acid sequences provided by GenBank Accession No. US 2007/0O82347 A1 Apr. 12, 2007

NM 016442 (PRI 23-Apr-2005) (see SEQ ID NOS:30 and sequences provided by GenBank Accession No. 31) and AF 183569 (PRI 29-Dec.-1999) (see SEQ ID NM 014314 (PRI 2-Apr-2006) (see SEQID NOS:274 and NOs:32 and 33) are used as the reference sequences for 275) are used as the reference sequences for DDX58 cDNA ARTS1 cDNA and protein, respectively. and protein, respectively. 0076) For MSR genomic DNA, the sequence provided by 0084. For CD39 genomic DNA, the sequences provided GenBank Accession No. AC025174 (PRI 28-Mar.-2002) is by GenBank Accession Nos. AL356632 (PRI 18-May-2005) used as a reference sequence, while the nucleotide and and AL365273 (PRI 18-May-2005) are used as a reference amino acid sequences provided by GenBank Accession No. sequence, while the nucleotide and amino acid sequence NM 002454 (PRI 22-Apr-2005) (see SEQ ID NOs:66 and provided by GenBank Accession No. NM 001776 (PRI 67) and NM 024010 (PRI 22-Apr-2005) (see SEQ ID 15-Oct.-2006) (see SEQ ID NOS:243 and 244) are used as NOs:68 and 69) are used as the reference sequences for the reference sequences for CD39 cDNA and protein, MSR cDNA and protein, respectively. respectively. 0077. For AKAP9 genomic DNA, the sequence provided 0085 For FKBP1a genomic DNA, the sequences pro by GenBank Accession No. AC003086 (PRI 21-Dec.-1999) vided by GenBank Accession Nos. AL136531 (PRI 18-May is used as a reference sequence, while the nucleotide and 2005) and AL109658 (PRI 18-May-2005) are used as a amino acid sequences provided by GenBank Accession No. reference sequence, while the nucleotide and amino acid NM 005751 (PRI 5-Jun-2005) (see SEQ ID NOs:90 and sequences provided by GenBank Accession No. 91) are used as the reference sequences for AKAP9 cDNA NM 000801 (PRI 6-Nov.-2005) (see SEQ ID NO:249 and and protein, respectively. 250) is used as the reference sequences for FKBP1 a cDNA 0078 For DNAJD1 genomic DNA, the sequence pro and protein, respectively. vided by GenBank Accession No. AL445217 (PRI 18-May 0086 For SRI genomic DNA, the sequences provided by 2005) is used as a reference sequence, while the nucleotide GenBank Accession Nos. AC003991 (PRI 4-Feb.-2000) and and amino acid sequences provided by GenBank Accession AC005075 (PRI 2-Oct.-2000) are used as a reference No. NM 013238 (PRI 24-May-2005) (see SEQ ID sequences, while the nucleotide and amino acid sequences NOs: 149 and 150) are used as the reference sequences for provided by GenBank Accession Nos. NM 003130 (PRI DNAJD1 cDNA and protein, respectively. 15-Jan.-2006) (see SEQID NO:253 and 254) are used as the 0079 For GOLPH4 genomic DNA, the sequence pro reference sequences for SRI cDNA and protein, respectively. vided by GenBank Accession No. AC117467 (PRI 1-Aug.- 0087. For XRRA1 genomic DNA, the sequences pro 2002) and GenBank Accession No. AC069243 (PRI vided by GenBank Accession Nos. AP000560 (PRI 15-Mar.- 28-SEP-2002) are used as a reference sequence, while the 2003) and AP001992 (PRI 15-Mar.-2003) are used as a nucleotide and amino acid sequences provided by GenBank reference sequences, while the nucleotide and amino acid Accession No. NM 014498 (PRI 22-Apr-2005) (see SEQ sequences provided by GenBank Accession Nos. ID NOS:156 and 157) are used as the reference sequences for XM 374912 (PRI 19-Feb.-2004) (see SEQID NO:257 and GOLPH4 cDNA and protein, respectively. 258) are used as the reference sequences for XRRA1 clNA 0080 For RABEP1 genomic DNA, the sequence pro and protein, respectively. vided by GenBank Accession No. NM 004703 (PRI 0088 For IRF5 genomic DNA, the sequences provided 8-Jun-2005) is used as a reference sequence, while the by GenBank Accession Nos. AC025594 (PRI 28-Nov.- nucleotide and amino acid sequences provided by GenBank 2000) are used as a reference sequences, while the nucle Accession No. NM 004703 (PRI8-Jun-2005) (see SEQID otide and amino acid sequences provided by GenBank NOs: 170 and 171) are used as the reference sequences for Accession Nos. NM 002200 (PRI 18-Oct.-2005) (see SEQ RABEP1 cDNA and protein, respectively. ID NO:280) are used as the reference sequences for IRF5 0081 For TAP2 genomic DNA, the sequence provided cDNA and protein, respectively. by GenBank Accession No. AL671681 (PRI 18-May-2005) 0089 For AMFR genomic DNA, the sequence provided is used as a reference sequence, while the nucleotide and by GenBank Accession No. AC092140 (PRI 3-Jan.-2004) is amino acid sequences provided by GenBank Accession No. used as a reference sequence, while the nucleotide sequences NM 000544 (PRI 10-Jun-2005) (see SEQ ID NO:202 and provided by GenBank Accession No. NM 001144 (PRI 203) and NM 018833 (PRI 10-Jun-2005) (see SEQ ID 27-Oct.-2004) (see SEQ ID NO: 1) and NM 138958 (PRI NO:204 and 205) are used as the reference sequences for 27-Oct.-2004) (SEQ ID NO:3) are used as the reference TAP2 cl DNA and protein, respectively. sequences for AMFR cDNA and protein, respectively. 0082 For NARG2 genomic DNA, the sequence provided by GenBank Accession No. AC087385 (PRI 29-Jul-2002) 0090. As used herein, the term “TLK1 nucleic acid” is used as a reference sequence, while the nucleotide and means a nucleic acid molecule the nucleotide sequence of amino acid sequences provided by GenBank Accession No. which is uniquely found in a TLK1 gene. That is, a “TLK1 NM 024611 (PRI 8-Jun-2005) (see SEQ ID NOS:230 and nucleic acid' is either a TLK1 genomic DNA or mRNA/ 231) are used as the reference sequences for NARG2 cDNA cDNA, having a naturally existing nucleotide sequence and protein, respectively. encoding a naturally existing TLK1 protein (wild-type or mutant form). The sequence of an example of a naturally 0083) For DDX58 genomic DNA, the sequences pro existing TLK1 nucleic acid is found in GenBank Accession vided by GenBank Accession Nos. AL161783 (PRI 18-May No. AB004885 (PRI 5-Feb-1999) (see SEQ ID NO:1). 2005) and AL353671 (PRI 18-May-2005) are used as a Other examples include nucleic acids provided by GenBank reference sequence, while the nucleotide and amino acid Accession Nos. AK091975 (PRI 30-Jan.-2004) (see SEQID US 2007/0O82347 A1 Apr. 12, 2007

NO:14), AKO90779 (PRI 30-Jan.-2004) (see SEQ ID 0097 As used herein, the term “MSR protein’ means a NO:15) and NM 012290 (PRI 23-Apr-2005) (see SEQ ID polypeptide molecule the amino acid sequence of which is NO:16). found uniquely in an MSR protein. That is, “MSR protein' 0.091 As used herein, the term “TLK1 protein’ means a is a naturally existing MSR protein (wild-type or mutant polypeptide molecule the amino acid sequence of which is form). The sequence of a wild-type form of a MSR protein found uniquely in a TLK1 protein. That is, “TLK1 protein’ is found in GenBank Accession No. NM 002454 (PRI is a naturally existing TLK1 protein (wild-type or mutant 22-Apr-2005) (see SEQID NO:67) and NM 024010 (PRI form). The sequence of a wild-type form of a TLK1 protein 22-Apr-2005) (see SEQ ID NO:69). is provided by GenBank Accession No. AB004885 (PRI 0.098 As used herein, the term “AKAP9 nucleic acid” 5-Feb.-1999) (see SEQ ID NO:2). Other examples include means a nucleic acid molecule the nucleotide sequence of amino acid sequences listed in GenBank Accession Nos. which is uniquely found in an AKAP9 gene. That is, an AK091975 (PRI 30-Jan.-2004), AKO90779 (PRI 30-Jan.- “AKAP9 nucleic acid” is either an AKAP9 genomic DNA or 2004) and NM 012290 (PRI 23-Apr-2005) (see SEQ ID mRNA/cDNA, having a naturally existing nucleotide NO:13). sequence encoding a naturally existing AKAP9 protein 0092. As used herein, the term “WARS2 nucleic acid” (wild-type or mutant form). The sequence of an example of means a nucleic acid molecule the nucleotide sequence of a naturally existing AKAP9 nucleic acid is found in Gen which is uniquely found in a WARS2 gene. That is, a Bank Accession No. NM 005751 (PRI 8-Jun-2005) (see “WARS2 nucleic acid” is either a WARS2 genomic DNA or SEQID NO:90), NM 147171 (PRI 8-Jun-2005) (see SEQ mRNA/cDNA, having a naturally existing nucleotide ID NO:92), NM 147185 (PRI 8-Jun-2005) (see SEQ ID sequence encoding a naturally existing WARS2 protein NO:93), NM 147166 (PRI 8-Jun-2005) (see SEQ ID (wild-type or mutant form). The sequence of an example of NO:94) and AK000270 (PRI 13-SEP-2003) (see SEQ ID a naturally existing WARS2 nucleic acid is found in Gen NO:95). Bank Accession No. NM 015836 (PRI 23-Apr-2005) (see 0099. As used herein, the term “AKAP9 protein” means SEQID NO:18) and NM 201263 (PRI 5-Jun-2005) (SEQ a polypeptide molecule the amino acid sequence of which is ID NO:20). found uniquely in an AKAP9 protein. That is, “AKAP9 0093. As used herein, the term “WARS2 protein” means protein’ is a naturally existing AKAP9 protein (wild-type or a polypeptide molecule the amino acid sequence of which is mutant form). The sequence of a wild-type form of an found uniquely in a WARS2 protein. That is, “WARS2 AKAP9 protein is found in GenBank Accession No. protein’ is a naturally existing WARS2 protein (wild-type or NM 005751 (PRI 8-Jun-2005) (see SEQ ID NO:91). mutant form). The sequence of a wild-type form of a 0100. As used herein, the term “DNAJD1 nucleic acid” WARS2 protein is found in GenBank Accession No. means a nucleic acid molecule the nucleotide sequence of NM 015836 (PRI 23-Apr-2005) (see SEQID NO:19) and which is uniquely found in a DNAJD1 gene. That is, a NM 201263 (PRI 5-Jun-2005) (SEQ ID NO:21). “DNAJD1 nucleic acid” is either a DNAJD1 genomic DNA 0094. As used herein, the term “ARTS1 nucleic acid” or mRNA/cDNA, having a naturally existing nucleotide means a nucleic acid molecule the nucleotide sequence of sequence encoding a naturally existing DNAJD1 protein which is uniquely found in an ARTS1 gene. That is, a (wild-type or mutant form). The sequence of an example of “ARTS1 nucleic acid” is either an ARTS1 genomic DNA or a naturally existing DNAJD1 nucleic acid is found in mRNA/cDNA, having a naturally existing nucleotide GenBank Accession No. NM 013238 (PRI 24-May-2005) sequence encoding a naturally existing ARTS1 protein (see SEQ ID NO:149). (wild-type or mutant form). The sequences of examples of 0101. As used herein, the term “DNAJD1 protein’ means naturally existing ARTS 1 nucleic acid are found in GenBank a polypeptide molecule the amino acid sequence of which is Accession No. NM 016442 (PRI 23-Apr-2005) (see SEQ found uniquely in a DNAJD1 protein. That is, “DNAJD1 ID NO:30) and AF 183569 (PRI 29-Dec.-1999) (SEQ ID protein’ is a naturally existing DNAJD1 protein (wild-type NO:32). or mutant form). The sequence of a wild-type form of a 0.095 As used herein, the term “ARTS1 protein’ means DNAJD1 protein is found in GenBank Accession No. a polypeptide molecule the amino acid sequence of which is NM 013238 (PRI 24-May-2005) (see SEQ ID NO:150). found uniquely in an ARTS1 protein. That is, “ARTS1 protein’ is a naturally existing ARTS1 protein (wild-type or 0102) As used herein, the term “GOLPH4 nucleic acid” mutant form). The sequence of a wild-type form of an means a nucleic acid molecule the nucleotide sequence of ARTS1 protein is found in GenBank Accession No. which is uniquely found in an GOLPH4 gene. That is, a NM 016442 (PRI 23-Apr-2005) (see SEQID NO:31) and “GOLPH4 nucleic acid” is either a GOLPH4 genomic DNA AF183569 (PRI 29-Dec-1999) SEQ ID NO:33). or mRNA/cDNA, having a naturally existing nucleotide sequence encoding a naturally existing GOLPH4 protein 0096. As used herein, the term “MSR nucleic acid” (wild-type or mutant form). The sequence of an example of means a nucleic acid molecule the nucleotide sequence of a naturally existing GOLPH4 nucleic acid is found in which is uniquely found in a MSR gene. That is, a “MSR GenBank Accession No. NM 014498 (PRI 22-Apr-2005) nucleic acid' is either an MSR genomic DNA or mRNA/ cDNA, having a naturally existing nucleotide sequence (see SEQ ID NO:156). encoding a naturally existing MSR protein (wild-type or 0103) As used herein, the term “GOLPH4 protein’ means mutant form). The sequence of an example of a naturally a polypeptide molecule the amino acid sequence of which is existing MSR nucleic acid is found in GenBank Accession found uniquely in an GOLPH4 protein. That is, “GOLPH4 No. NM 002454 (PRI 22-Apr-2005) (see SEQID NO:66) protein’ is a naturally existing GOLPH4 protein (wild-type and NM 024010 (PRI 22-Apr-2005) (see SEQID NO:68). or mutant form). The sequence of a wild-type form of a US 2007/0O82347 A1 Apr. 12, 2007

GOLPH4 protein is found in GenBank Accession No. (wild-type or mutant form). The sequence of an example of NM 014.498 (PRI 22-Apr-2005) (see SEQ ID NO:157). a naturally existing DDX58 nucleic acid is found in Gen 0104. As used herein, the term “RABEP1 nucleic acid” Bank Accession No. NM 014314 (PRI 2-Apr-2006) (see means a nucleic acid molecule the nucleotide sequence of SEQ ID NO:274). which is uniquely found in an RABEP1 gene. That is, a 0111. As used herein, the term “DDX58 protein’ means “RABEP1 nucleic acid” is eitheran RABEP1 genomic DNA a polypeptide molecule the amino acid sequence of which is or mRNA/cDNA, having a naturally existing nucleotide found uniquely in a DDX58 protein. That is, “DDX58 sequence encoding a naturally existing RABEP1 protein protein’ is a naturally existing DDX58 protein (wild-type or (wild-type or mutant form). The sequence of an example of mutant form). The sequence of a wild-type form of a DDX58 a naturally existing RABEP1 nucleic acid is found in protein is found in GenBank Accession No. NM 014314 GenBank Accession No. NM 004703 (PRI 8-Jun-2005) (PRI 2-Apr-2006) (see SEQ ID NO:275). (see SEQ ID NO:170). 0112. As used herein, the term “CD39 nucleic acid” 0105. As used herein, the term “RABEP1 protein’ means means a nucleic acid molecule the nucleotide sequence of a polypeptide molecule the amino acid sequence of which is which is uniquely found in a CD39 gene. That is, a “CD39 found uniquely in an RABEP1 protein. That is, “RABEP1 nucleic acid' is either a CD39 genomic DNA or mRNA/ protein’ is a naturally existing RABEP1 protein (wild-type cDNA, having a naturally existing nucleotide sequence or mutant form). The sequence of a wild-type form of a encoding a naturally existing CD39 protein (wild-type or RABEP1 protein is found in GenBank Accession No. mutant form). The sequence of an example of a naturally NM 004703 (PRI 8-Jun-2005) (see SEQ ID NO:171). existing CD39 nucleic acid is found in GenBank Accession 0106) As used herein, the term “TAP2 nucleic acid” Nos. NM 001776 (PRI 15-Jan.-2006) (see SEQ ID means a nucleic acid molecule the nucleotide sequence of NO:243). which is uniquely found in a TAP2 gene. That is, a “TAP2 0113 As used herein, the term “CD39 protein’ means a nucleic acid' is either a TAP2 genomic DNA or mRNA/ polypeptide molecule the amino acid sequence of which is cDNA, having a naturally existing nucleotide sequence found uniquely in a CD39 protein. That is, “CD39 protein' encoding a naturally existing TAP2 protein (wild-type or is a naturally existing CD39 protein (wild-type or mutant mutant form). The sequence of an example of a naturally form). The sequence of a wild-type form of a CD39 protein existing TAP2 nucleic acid is found in GenBank Accession is found in GenBank Accession No. NM 001776 (PRI No. NM 000544 (PRI 10-Jun-2005) (see SEQID NO:202) 15-Jan.-2006) (see SEQ ID NO:244). and NM 018833 (PRI 10-Jun-2005) (see SEQ ID 0114. As used herein, the term “FKBP1a nucleic acid” NO:204). means a nucleic acid molecule the nucleotide sequence of 0107 As used herein, the term “TAP2 protein” means a which is uniquely found in a FKBP1 a gene. That is, a polypeptide molecule the amino acid sequence of which is “FKBP1a nucleic acid” is either a FKBP1a genomic DNA or found uniquely in a TAP2 protein. That is, “TAP2 protein’ mRNA/cDNA, having a naturally existing nucleotide is a naturally existing TAP2 protein (wild-type or mutant sequence encoding a naturally existing FKBP1a protein form). The sequence of a wild-type form of a TAP2 protein (wild-type or mutant form). The sequence of an example of is found in GenBank Accession No. NM 000544 (PRI a naturally existing FKBP1 a nucleic acid is found in Gen 10-Jun-2005) (see SEQID NO:203) and NM 018833 (PRI Bank Accession No. NM 000801 (PRI 6-Nov.-2005) (see 10-Jun-2005) (see SEQ ID NO:205). SEQ ID NO:249). 0108) As used herein, the term “NARG2 nucleic acid” 0115. As used herein, the term “FKBP1a protein’ means means a nucleic acid molecule the nucleotide sequence of a polypeptide molecule the amino acid sequence of which is which is uniquely found in an NARG2 gene. That is, a found uniquely in an FKBP1 a protein. That is, “FKBP1a “NARG2 nucleic acid” is either an NARG2 genomic DNA protein’ is a naturally existing FKBP1a protein (wild-type or or mRNA/cDNA, having a naturally existing nucleotide mutant form). The sequence of a wild-type form of an sequence encoding a naturally existing NARG2 protein FKBP1a protein is found in GenBank Accession Nos. (wild-type or mutant form). The sequence of an example of NM 000801 (PRI 6-Nov.-2005) (see SEQ ID NO:250). a naturally existing NARG2 nucleic acid is found in Gen 0116. As used herein, the term “SRI nucleic acid' means Bank Accession No. NM 024611 (PRI 8-Jun-2005) (see a nucleic acid molecule the nucleotide sequence of which is SEQ ID NO:230). uniquely found in an SRI gene. That is, an "SRI nucleic 0109) As used herein, the term “NARG2 protein” means acid” is either an SRI genomic DNA or mRNA/cDNA, a polypeptide molecule the amino acid sequence of which is having a naturally existing nucleotide sequence encoding a found uniquely in an NARG2 protein. That is, “NARG2 naturally existing SRI protein (wild-type or mutant form). protein’ is a naturally existing NARG2 protein (wild-type or The sequences of exemplary naturally existing SRI nucleic mutant form). The sequence of a wild-type form of a acid are found in GenBank Accession No. NM 003130 NARG2 protein is found in GenBank Accession No. (PRI 15-Jan.-2006) (SEQ ID NO:253). NM 024611 (PRI 8-Jun-2005) (see SEQ ID NO:231). 0117. As used herein, the term "SRI protein’ means a 0110. As used herein, the term “DDX58 nucleic acid” polypeptide molecule the amino acid sequence of which is means a nucleic acid molecule the nucleotide sequence of found uniquely in an SRI protein. That is, an “SRI protein' which is uniquely found in a DDX58 gene. That is, a is a naturally existing SRI protein (wild-type or mutant “DDX58 nucleic acid” is either a DDX58 genomic DNA or form). The sequence of a wild-type form of an SRI protein mRNA/cDNA, having a naturally existing nucleotide is found in GenBank Accession No. NM 003130 (PRI sequence encoding a naturally existing DDX58 protein 15-Jan.-2006) (SEQ ID NO:254). US 2007/0O82347 A1 Apr. 12, 2007

0118. As used herein, the term “XRRA1 nucleic acid” 1-35. Exemplary TLK1, WARS2, ARTS2, MSR, AKAP9, means a nucleic acid molecule the nucleotide sequence of DNAJD1, GOLPH4, RABEP1, TAP2, NARG2, DDX58, which is uniquely found in an XRRA1 gene. That is, an CD39, FKBP1a, SRI, XRRA1, IRF5 and AMFR gene “XRRA1 nucleic acid” is either an XRRA1 genomic DNA sequences spanning the SNPs in the tables are provided in or mRNA/cDNA, having a naturally existing nucleotide the sequence listing. sequence encoding a naturally existing XRRA1 protein 0.125 The nucleotide positions are assigned by aligning (wild-type or mutant form). The sequences of exemplary the variant allele sequences to the above-identified cDNA naturally existing XRRA1 nucleic acid are found in Gen reference sequence and genomic reference sequence. Spe Bank Accession No. XM 374912 (PRI 19-Feb.-2004) cifically, the nucleotide position of a SNP is indicated (SEQ ID NO:257). relative to the nearest exon. As a general example, EX6(a)51 0119) As used herein, the term “XRRA1 protein” means means the SNP is located within exon 6 of a gene at the 51 a polypeptide molecule the amino acid sequence of which is nucleotide position counting in a 5' to 3’ direction from the found uniquely in an XRRA1 protein. That is, an “XRRA1 5' end of exon 6 with the 5' end nucleotide of exon 6 being protein’ is a naturally existing XRRA1 protein (wild-type or the 1 position. EX7(a)+14 means the SNP is located within mutant form). The sequence of a wild-type form of an the intron immediately 3' to exon 7 of a gene at the 14" XRRA1 protein is found in GenBank Accession No. nucleotide position counting in a 5' to 3’ direction from the XM 374912 (PRI 19-Feb.-2004) (SEQ ID NO:258). 5' end of that intron with the 5' end nucleotide of that intron being the 15 nucleotide position. EX13(a)-27 means the 0120) As used herein, the term “IRF5 nucleic acid” SNP is located within the intron immediately 5' to exon 13 means a nucleic acid molecule the nucleotide sequence of of the gene at the 27" nucleotideposition counting in a 3’ to which is uniquely found in an IRF5 gene. That is, an “IRF5 5' direction from the 3' end nucleotide of the intron with the nucleic acid' is either an IRF5 genomic DNA or mRNA/ 3' end nucleotide of that intron being the 15 nucleotide cDNA, having a naturally existing nucleotide sequence position. Likewise, EX1(a)-761 means that the SNP is encoding a naturally existing IRF5 protein (wild-type or located at the 761 nucleotide position upstream from the 5' mutant form). The sequences of exemplary naturally exist end nucleotide of exon 1, with the first intron/regulatory ing IRF5 nucleic acid are found in GenBank Accession No. nucleotide immediately 5' to exon 1 being the 1 nucleotide NM 002200 (PRI 18-Oct.-2005) (see SEQ ID NO:280). position. 0121. As used herein, the term “IRF5 protein’ means a 0.126 The amino acid substitutions caused by the nucle polypeptide molecule the amino acid sequence of which is otide variants (SNPs) are also identified according to con found uniquely in an IRF5 protein. That is, an “IRF5 ventional practice. For example, A160V means the amino protein’ is a naturally existing IRF5 protein (wild-type or acid variant at position 160 is V in contrast to A in the mutant form). The sequence of a wild-type form of an IRF5 reference sequence identified above with the N-terminus protein is found in GenBank Accession No. NM 002200 amino acid being at position 1. (PRI 18-Oct.-2005) (see SEQ ID NO:281). 0127. In some cases, the nucleotide positions and nucle 0122). As used herein, the term “AMFR nucleic acid” otide variant identities are provided by reference to corre means a nucleic acid molecule the nucleotide sequence of sponding reference cluster ID (rSH) assigned in the public which is uniquely found in an AMFR gene. That is, an dbSNP database accessible at the NCBI website, or by “AMFR nucleic acid” is either an AMFR genomic DNA or chromosome locations. mRNA/cDNA, having a naturally existing nucleotide sequence encoding a naturally existing AMFR protein (wild 0128. Thus, the SNPs identified according to the present type or mutant form). The sequences of exemplary naturally invention are associated with “expression phenotypes in existing AMFR nucleic acid are found in GenBank Acces humans. That is, it has been discovered that the baseline sion No. NM 001144 (PRI 27-Oct.-2004) (see SEQ ID expression level of the genes in Tables 1-35 in human cells NO:291) and NM 138958 (PRI 27-Oct.-2004) (SEQ ID is an inheritable "quantitative trait” with genetic determi NO:293). nants. Furthermore, it has been Surprisingly discovered that the SNPs and haplotypes in accordance with the present 0123. As used herein, the term “AMFR protein’ means a invention are associated with the "quantitative trait”, i.e., the polypeptide molecule the amino acid sequence of which is mRNA level of the genes in human cells. Thus, the SNPs found uniquely in an AMFR protein. That is, an “AMFR and haplotypes are particularly useful in predicting the gene protein’ is a naturally existing AMFR protein (wild-type or expression in an individual. mutant form). The sequence of a wild-type form of an AMFR protein is found in GenBank Accession No. 0129. In response to DNA damage cells initiate a series of NM 001144 (PRI 27-Oct.-2004) (see SEQID NO:292) and processes that prevent replication of damaged DNA and NM 138958 (PRI 27-Oct.-2004) (SEQ ID NO:294). maintain integrity of the genome. The DNA damage check point induces cell cycle arrest, allowing for repair mecha 2. Nucleotide and Amino Acid Variants nisms to occur before transmission of damaged chromo Somes. DNA damage can be caused by a variety of agents 0124 Thus, in accordance with the present invention, including ultraviolet radiation (UV), mutagenic chemicals, genetic variants, i.e., single nucleotide polymorphisms radiation, free radicals and teratogens. Cancer and heart (SNPs) and/or haplotypes have been discovered in the disease are among the diseases associated with damage to TLK1, WARS2, ARTS2, MSR, AKAP9, DNAJD1, DNA. TLK1 has been identified as a regulator of the DNA GOLPH4, RABEP1, TAP2, NARG2, DDX58, CD39, damage checkpoint system. TLK1 is the mammalian FKBP1a, SRI, XRRA1, IRF5 and AMFR genes. The iden homolog of the plant Tousled gene which regulates flower tified SNPs and/or haplotypes are summarized in Tables development. TLK1 is 84% similar to Tousled on an amino US 2007/0O82347 A1 Apr. 12, 2007 acid level and shares its kinase activity. TLK1 is a 81.9 kD 0132) An isoform of TLK1, named SNAK for SNARE nuclear localized kinase having 5-domains including an kinase, was shown to phosphorylate SNAP-23, a component N-terminus nuclear localization signal, a protein kinase of the SNARE complex. SNAP-23 is the ubiquitiously ATP-binding motif, a nucleotide binding motif, and a single expressed homolog of the neuron-specific SNAP-25 and is catalytic domain near the C-terminus. See Sillje et al., essential for the regulation of exocytosis in several cell EMBO. J., 18(20):5691-702 (1999). TLK1 phosphorylates types. For example, fusion of GLUT4 containing vesicles ASF1, a chromatin assembly factor, implicating it in the with the plasma membrane involves the target membrane regulation of chromatin remodeling. Mammalian TLKS have SNAREs syntaxin 4 and SNAP-23 and the vesicle-associ been implicated in regulation of chromatin remodeling ated SNARE VAMP2. SNAP-23 is palmitoylated post through the observation that they phosphorylate the chro translationally and this acylated form readily associates with matin assembly factor ASF1. ASF1 synergizes with another membranes. Phosphorylation increases the stability of chromatin assembly factor, CAF1, in replication- and repair SNAP-23 and promotes the formation of SNARE com coupled chromatin remodeling. See Sillje et al., Curr Biol., plexes. Expression levels of TLK1 could therefore influence 11(13):1068-73 (2001). the kinetics of SNARE assembly and contribute to SNARE associated metabolic disorders. See Cabaniols et al., Mol. 0130 Underlining the importance of TLK1 in the pres Biol. Cell, 10(12):4033-4041 (1999). ervation of genomic integrity, the normally active TLK1 is inhibited in the event of DNA damage such as a double 0.133 WARS2 is the mitochondrial form of tryptophanyl strand break (DSB). Inhibition of TLK depends on the action tRNA synthetase, the enzyme that links the nucleotide of the DNA damage checkpoint system including the kinases triplets in the genetic code to form amino acid units by ATM (ataxia telangiectasia mutated) and ATR (ataxia and catalyzing the loading of the tryptophan-specific tRNA with Rad3 related). ATM is a key regulator in response to ionizing the amino acid tryptophan. WARS2 is a 360-amino acid 40.1 radiation (IR), while ATR induces cell cycle arrest in kDa C. dimer protein of the class IaaRSs. See Jorgensen et response to a wide range of agents producing DNA double al., J. Biol. Chem., 275(22):16820-16826 (2002). Nearly 100 Strand breaks. Both kinases relay the checkpoint signal disease-correlated mutations in the mitochondrial genome through phosphorylation of checkpoint kinases: Chk2 (also are known to be located in mitochondrial tRNA genes. known as RadS3) and Chk1. Inhibition of TLK1 in response Mitochondrial dysfunction is a mechanism in the progres to IR depends on ATM and Chk1, as well as the sensor sion of neurodegenerative disorders such as Friedeich's protein NBS1. Expression of a dominant-negative kinase ataxia, Huntington's disease, Alzheimer's disease amyo mutant of TLK1 results in chromosome missegregation and trophic lateral sclerosis (ALS) and Parkinson's disease. aneuploidy, underlining the importance of TLK1 in preserv Although no specific disorders have been associated with ing genomic integrity. Experiments using mouse cell lines WARS2 mutation, variations in the expression levels of have shown that TLK1 overexpression increases cell resis WARS2 are likely to contribute to disorders associated with tance to DNA damage caused by ionizing radiation. See mutations in the corresponding mitochondrial tRNA gene. Sunalava-Dossabhoy et al., BMC Cell Biol., 4(1):16 (2003). Thus, polymorphisms correlating with expression levels of Thus, expression levels of TLK1 affect the ability to control WARS2 are useful to predict of detect susceptibility to DNA damage and can be used to determine resistance to the neurodegenerative disease. Such as Friedreich's ataxia, Hun DNA damage and Susceptibility to diseases resulting from tington's disease, Alzheimer's disease, ALS and Parkinson's Such carcinogens. Further, common cancer treatments that disease, in an individual. function by inducing DNA damage will be affected by TLK1 0.134 Polymorphisms in mitochondrial DNA have also levels. been linked to mitochondria dysfunction associated with cardiovascular disease. Such diseases include dilated and 0131 Histone H3, a modifier of chromatin condensation, is present in the cytosol at the highest levels during active hypertrophic cardiomyopathy, cardiac conduction defects DNA replication. See Senshu et al., Eur J. Biochem., and Sudden death, ischemic and alcoholic cardiomyopathy, 146(2):261-6 (1985). Phosphorylation of histone H3 influ and myocarditis. These abnormalities result in dysfunction ences transcription, chromosome condensation, DNA repair in oxidative phosphorylation and fatty acid beta-oxidation. and apoptosis. TLK1 has been shown to phosphorylate See Marin-Garcia, J. and Goldenthal, M. J., J. Card. Fail., histone H3 in vitro and in vivo. See Sunavala-Dossabhoy et 8(5):347-61 (2002). Thus, SNPs correlating with WARS2 al., BMC Cell Biol., 4(1): 16 (2003). Downregulation of mRNA expression levels are useful as a means of predicting histone H3 mRNA levels occurs in parallel with the inhibi or detecting Susceptibility to cardiovascular disease in an tion of DNA synthesis during S-phase upon DNA damage. individual. See Zhao, J., Cell Cycle, 3(6):695-7 (2004). Levels of TLK1 0135) An N-terminally truncated WARS2 fragment, are elevated 9.4 times in patients with stage I to II breast T2-TrpRS, is a potent antagonist of vascular endothelial cancer. See Norton et al., J Surg Res., 116(1):98-103 (2004). growth-factor induced angiogenesis. Particularly, T2-TrpRS This suggests that TLK1 is linked to the S-phase DNA regulates extracellular signal activated protein kinase, Akt, damage checkpoint and DNA replication in the cell. Thus, and ECNO synthase activation pathways involved in angio increased H3 histone phosphorylation as a result of TLK1 genesis, cytoskeletal reorganization, and shear stress-re overexpression causes chromosome instability and, thus, sponsive gene expression. Angiogenesis stimulating gene may play a role in carcinogenesis. Accordingly, polymor expression was shown to be linked to tumor progression in phisms influencing expression levels of TLK1 would be nude mice. See Yoneda et al., J. Natl. Cancer Inst., 90:447 useful in predicting cancer progression and response to 454 (1998). Expression of T2-TrpRS blocks vascular endot radiation treatment as well as susceptibility to DNA damage helial growth factor-stimulated angiogenesis. Higher con by ionizing radiation. See Li et al. Oncogene., 2006):726-38 centration of T2-TrpRS further decreased activity of VEGF (2001). induced angiogenesis. See Otani et al., Proc. Natl. Acad. Sci. US 2007/0O82347 A1 Apr. 12, 2007

USA., 99(1):173083 (2002). Proteins demonstrating a simi cells. See Wantanabe et al., Clin. Cancer Res., 9(17):6497 lar angiogenesis inhibiting effect are currently used in the 503 (2003). Thus, SNPs associated with ARTS1 mRNA treatment of cancer to prevent the spread of cancer cells by expression levels are useful as a means of predicting or blood vessel growth. See Langer, et al., Proc. Natl. Acad. detecting cancer Susceptibility, predicting cancer progres Sci., 77(7):4331-5 (1980). As T2-TrpRS is a naturally occur sion in an individual as well as and predicting patient ring protein, it provides an advantage as a potentially response to cancer treatment. nonimmunogenic compound for the treatment of cancer. See 0140 Expression of ARTS1 in Chinese hamster ovary Otani et al., Proc. Natl. Acad. Sci. USA., 99(1):173083 cells showed that ARTS1 hydrolyzes angiotensin II, a pro (2002). tein involved in the regulation of blood pressure. At high 0136 IFN-Y has been shown to be involved in an anti levels, angiotensin induces hypertension, cardiac hypertro tumorigenic signaling pathway making it useful in the phy, myocardial damage and coronary heart disease. See prognosis and therapy of cancer. See Blanck, G., Arch. Caulfield et al., N. Engl. J. Med., 330(23):1629-33 (1994) Immunol. Ther. Exp. 50(3):151-8 (2002). T2-TrpRS shows and Finkenberg et al., J. Hypertens., 23(2):375-80 (2005). high expression in the presence of IFN-y. T2-TrpRS is Treatment of patients with angiotensin-enzyme converting cleaved by PMN elastase protein, which is expressed in inhibitor A-I was shown to reduce death in ischemia human colorectal cancer, breast cancer and non-Small cell patients. See Zuliana et al., J. Gerontol. A. Biol. Sci. Med. lung cancers (NSCLCs). The resulting truncated protein, Sci., 60(4):463-5 (2005). Thus, SNPs associated with TrpTS, acts as an angiostatic inhibitor slowing tumor ARTS1 mRNA expression are useful to predict and detect growth. See Wakasugi et al., Proc. Natl. Acad. Sci. USA., Susceptibility to heart disease in an individual. 99(1):173-177 (2002). Accordingly, the SNPs associated 0.141 Cell surface antigens detect and eliminate foreign with WARS2 expression levels can be used to predict or cells such as those virally infected or tumorigenic. Before detect cancer Susceptibility, to predict cancer prognosis in an transport to the cell Surface, antigen precursor proteins are individual. synthesized in the cells endoplasmic reticulum (ER). Unprocessed precursor peptides bind on the Surface of major 0137 ARTS1 is a 120 kD type II integral membrane histocompatibity complex (MHC) where ARTS1 has been aminopeptidase critical in the metabolism of proteins shown to trim extra terminal residues from precursor pro involved in processes Such as blood pressure regulation, teins thereby creating 8-11 residue peptide fragments. These hypertension pathogenesis and immune response. ARTS1 fragments are then transported to the cell Surface facilitating creates bioactive peptides through hydrolysis of various cell recognition and elimination of virally infected cells. In inactive peptides within the ER. ARTS1 contains an N-ter other words, ARTS1 hydrolyzes proteins creating functional minal signal peptide, 5 potential N-glycosylation sites, a antigenic precursors necessary for immune system cell rec potential membrane-spanning domain, and a zinc-binding ognition. ARTS1 overexpression stimulates processing and motif. See Hattori et al., J. Biochem., 125:931-938 (1999). presentation of antigenic precursors in the ER demonstrating 0138 Coimmunoprecipitation assays have shown that the importance of ARTS1 levels in immune response. Fur ARTS1 binds TNFR1 to form a complex that promotes ther, agents that block precursor trimming in the ER have TNFR1 ecto-domain shedding. TNFR1 is a tumor necrosis been shown to inhibit ARTS1 function. See Cui, et al., J. factor that, in its cleaved State, is a multifunctional cytokine Clin. Invest., 110(4):515-526 (2002). Accordingly, ARTS1 involved in the regulation of processes such as inflammatory levels could be used to predict immune response in an response, immunoregulation, cytotoxicity, antiviral actions individual, especially that associated with viral infection. and transcriptional regulation of genes. See Vilcek and Lee, 0142. MSR is an essential enzyme in folate/cobalamin J. Biol. Chem., 266:7313-7316 (1991). ARTS1 levels metabolism. MSR functions by recycling cobalamin, a directly correlate with TNFR1 shedding. Overexpression of cofactor necessary for activation of the enzyme methionine ARTS1 mRNA results in increased TNFR shedding and synthetase (MS), which catalyzes the remethylation of diminished membrane-associated TNFR1. Conversely, the homocysteine to methionine. See Wilson et al., Human expression of anti-sense ARTS1 mRNA leads to decreased Molecular Genetics, 8(11):2009-2016 (1999). As cobalamin TNFR1 shedding and membrane associated ARTS1 as well is used, it becomes oxidized rendering it inactive. See as increased membrane associated TNFR1. See Cui et al., J Banerjee, R., Chem Biol., 4, 175-186 (1997). MSR catalyzes Clin Invest., 110(4):515-26 (2002). TNFR1 shedding defi regeneration of cobalamin to its active state where it can be ciencies have been associated with autoimmune diseases used as a cofactor activating MS. Active MS is necessary for such as endotoxic shock, TNF-dependent arthritis, and catalyzing the final step in methionine synthesis. MSR encephalomyelitis. See Xanthoulea et al., J. Exp. Med. polymorphisms S175 was shown to be a genetic determinant 200(3):367-76 (2004). In view of the above, SNPs associ of plasma homocysteine levels. This polymorphism has ated with ARTS1 mRNA levels could be useful in the been linked to premature coronary artery disease, Down's prediction and detection of susceptibility to autoimmune and syndrome and neural tube defects. See Gaughan et al., inflammatory disease in humans. Atherosclerosis, 157(2): 451-6 (2001) and Olteanu et al., 0139 Activation of vascular endothelial growth factor Biochemistry, 43(7): 1988-97 (2004) and Bosco et al., Am. J. (VEGF) initiates cell proliferation and is a hallmark of Med. Genet. A., 121(3):219-24 (2003). Similarly, MSR tumor progression. Angiotensin II exposure induces VEGF mutations resulting in cobalamin deficiency have been activity in several cell types. Overexpression of ARTS1 in shown to cause homocystinuria, hyperhomocysteinemia and human endometrial carcinoma cells inhibited angiotensin II hypomethioninemia. See Watkins et al., Am. J. Hum. Genet., stimulated VEGF expression, Suggesting that elevated 71(1):143-153 (2002). ARTS1 levels reduce the amount of functional angiotensin 0.143 Homocysteine is produced during the metabolism II and suppress the proliferative effect of VEGF on tumor of methionine and can be remethylated to methionine US 2007/0O82347 A1 Apr. 12, 2007 through the action of MS. Elevated levels of homocysteine structural changes in the Golgi apparatus. See Larocca et al., (hyperhomocysteinemia) have been linked to cardiovascular Mol. Biol. Cell, 15(6):2771-81 (2004). Such structural disease, atherosclerosis, recurrent arterial and venous throm changes in Golgi apparatus have a role in the pathogenesis bosis and premature coronary artery disease. See Cattaneo, of AD, ALS and neurodegeneration caused by aging. Par M., Thromb Haemost., 81(2):165-76 (1999). MSR defi ticularly, fragmentation of the Golgi apparatus in motor ciency causes hyperhomocysteinemia, hypomethioninemia neurons has been associated with Alzheimer's disease (AD), and megaloblastic aneimia showing the effect of MSR levels amyotrophic lateral Sclerosis (ALS) and aging. See Steiber on homocysteine metabolism. See Wilson, et al., Hum. Mol. et al., Am. J. Pathol., 148(2):355-60 (1996). Defects in the Genet., 8(11):2009-2016 (1999). Studies have also shown an structure of the Golgi apparatus are found in the ballooned association of hyperhomocysteinaemia with neural tube neurons commonly found in those diagnosed with AD, defects such as spina bifida. See Mills et al., Lancet, dementia, Creutzfeldt-Jakob disease and Pick's disease. See 345(8943):149-51 (1995) and D'Angelo et al., Haemato Aoki et al., Acta. Neuropathol. (Berl). 106(5):436-40 logica, 82(2):211-9 (1997). Children with Down's syndrome (2003). Thus, SNPs associated with mRNA expression lev have significantly lower plasma levels of homocysteine. See els are useful to detect or predict susceptibility in an indi Pogribna et al., Am. J. Hum. Genet., 69(1):88-95 (2001). vidual to AD, ALS, neurodegeneration caused by aging, Wild-type minigene expression of MSR in patients having dementia, Creutzfeldt-Jakob disease and Pick's disease. cb1E type homocystinuria resulted in a four-fold increase in MSR-facilitated methionine synthesis. This demonstrates 0147 Irregularities in centromsomes have been linked to the association of MSR levels with the conversion of cancer development due to their central role in chromosome homocysteine to methionine. See Zavadakova et al., Hum. segregation, irregularities. See Kong et al., Drug News Mutat., 25(3):239-47 (2005). Accordingly, SNPs associated Perspect., 17(3):195-200 (2004). Over-expression of with MSR expression levels are useful as markers for AKAP9 resulted in an increase in the number of cen determining or predicting relative plasma homocysteine, trosomes in Chinese hamster ovary cells. See Nishimura et methionine and cobalamin levels, and for diagnosing and/or al., Gene Cells, 10(1):75-86 (2005). Experiments have predicting diseases and disorders associated with aberrant shown that an increased number of centrosomes can be plasma homocysteine, methionine and cobalamin levels. In correlated with tumor progression. Like many known tumor addition, the SNPs are also useful as markers for detecting supressors, AKAP9 localized to the centrosomes demon or predicting a predisposition to hyperhomocysteinemia, strating that it likely regulates chromosome duplication and cardiovascular disease, atherosclerosis, recurrent arterial function. See Fisk et al., Curr. Opin. Cell Biol., 14(6): 700-5 and venous thrombosis and premature coronary artery dis (2002). The increase in centrosome number in response to ease, neural tube defects and Down's syndrome. The SNPs AKAP9 expression Suggests an association with the risk of may also be useful in determining prognosis of hyperho developing cancer and with tumor progression. Thus, SNPs mocysteinemia, cardiovascular disease, atherosclerosis, associated with AKAP9 mRNA expression are useful as a recurrent arterial and venous thrombosis and premature means of detecting or predicting an individual’s Suscepti coronary artery disease, neural tube defects and Down's bility to cancer and tumor progression. syndrome in an individual. 0.148 Cyclic AMP-dependent kinase signaling abnor 0144) MSR facilitated methionine metabolism has also malities have been associated with depression and Symp been associated with cancer cell proliferation. A number of toms of depression. See Shelton et al. Int. J. Neuropsychop cancer cell types are methionine dependent. In other words, harmacol. 3:187-192 (1999) reported that reduced PKA in the cells are unable to grow on a medium where methionine fibroblasts was associated with melancholic major depres has been replaced with homocysteine precursor. The dou sion. Dwivedi et al. Biol. Psychiatry 56(1):30-40 (2004) bling time of non-Small lung cell cancer lines was shown to reported that PKA levels were altered in the brains of learned have a significant association with levels of methionine helpless rats. Perera et al. CNS Spectrums 6(7):565-572 synthetase. See Zhang et al., Cancer Res., 65(4): 1554-60 (2001) discusses the potential roles of PKA in depression (2005). Since the SNPs and haplotypes described here are and antidepressants. Thus, AKAP9 mediated signaling may associated with the expression level of MSR, they can be be involved in the etiology of depression by modulating used to predict cancer Susceptibility and prognosis in PKA signaling. patients. 0149 One splice variant of AKAP9 has 3,908 amino acids, and there are at least five other different AKAP9 0145 The AKAP9 gene is one of a family of scaffolding isoforms produced by alternative splicing. An alternative proteins that are critical for the subcellular distribution and splice variant of AKAP9 consisting of 1,642 residues is catalytic activity of the signaling mediator protein kinase A. found at neuronal and neuromuscular synapses. It specifi AKAP9 protein has been shown to regulate ion channel cally interacts with the N-methyl-D-aspartate (NMDA) activity, synaptic transmission and cell motility. Also known receptor (NR1) in brain, and may function to attach NR1 to as AKAP350, AKAP450 and CGNAP, the 350-450 kDa the postsynaptic cytoskeleton. It also binds to PKA and to protein has been shown to be localized to the centrosomes type I protein phosphatase (PP1), leading to the conclusion and the Golgi apparatus. See Steadman et al., J. Biol. Chem., that it is an AKAP that functions to bring together NR1 and 277(33):30165-76 (2002). its regulatory enzymes, thus regulating NR1 channel activity 0146 The Golgi apparatus functions in neurons by pro (Lin et al. J. Neuroscience 18:2012-2027 (1998)). Increases cessing polypeptides important in fast axoplasmic transport. in expression levels of NMDA receptor subunits and asso AKAP9 is expressed and interacts with CIP4 at the Golgi ciated intracellular proteins have been observed in patients apparatus. Disruption of the AKAP9-CIP4 interaction with Schizophrenia, bipolar disorder and major depression through expression of the CIP4 binding domain in AKAP9 (see, e.g., Nudmamud-Thanoi et al. Neurosci. Lett. 30:173-7 or silencing AKAP9 expression by RNA interference causes (2004); Clinton et al. Neuropsychopharmacology US 2007/0O82347 A1 Apr. 12, 2007

29(7): 1353-62 (2004); and Heresco-Levy et al. Eur: Neu 22):3887-8 (2002) and Muller et al., Ann. N.Y. Acad. Sci., ropsychopharmacol., 8(2):141-52 (1998)). This link 1022:44-9 (2004). Loss of heterozygosity and PCR studies between AKAP9 and the depression phenotype demon confirmed that MCJ expression is suppressed by methyla strates that SNPs associated with AKAP9 mRNA expression tion, which can be reduced by methyltransfer inhibitors. are useful to predict or detect susceptibility to depression in These results suggest a role of MCJ as a tumor Suppressor. an individual. See Starthdee et al., Carcinogenesis, 25(5):693-701 (2004). 0150. In the cardiac myocyte several AKAP proteins are MCJ overexpression performed through colony-forming involved in regulating 31 adrenergic receptor-induced, assays led to increased sensitivity to the anti-tumor drugs cAMP-dependent signaling mediated by PKA. Repolariza pacilitaxel, topotecan and cisplatin. Moreover, loss of MCJ tion of the cardiac action potential at the plasma membrane expression has been correlated with resistance to these types occurs via ion flow through potassium channels during the of drugs. See Shridhar et al., Cancer Research, 61:4258-65 QT interval of the cardiogram. Voltage-gated potassium (May 2001). As such, SNPs associated with expression channel 1 (KCNQ1) encodes a subunit of the potassium levels of DNAJD1 can be used as markers to predict or channel required for the delayed rectifier K+ current (I). detect cancer in a patient as well as to predict the effective This subunit is mutated in heritable forms of the long QT ness of anti-tumor agents in the treatment of cancer. syndrome, a disease characterized by prolonged QT inter 0153 Ataxin-1 aggregation and astrocyte injury have vals and associated with arrhythmias. The slow component been implicated in neurodegeneration. See Forman et al., J of the I current (I) is regulated by PKA. The yotiao splice Neurosci., 25(14):3539-50 (2005) and Cummings et al., form of AKAP9 has been found complexed to KCNO1. Philos. Trans. R. Soc. Lond B. Biol. Sci., 354(1386): 1079 Regulation of KCNO1 by PKA and protein phosphatase PP1 81 (1999). Aggregation of insoluble proteins such as requires interaction of KCNQ1 with yotiao through a leucine ataxin-1 has been associated with neurodegenerative dis Zipper motif. Congenital long QT syndrome is characterized eases such as Huntington's disease, Alzheimer's disease, by ventricular fibrillation with prolonged QT intervals and Parkinson's disease, the prion disorders, dentatorubral-pal associated with increased risk of Sudden death. One muta lidoluysian atrophy (DRPLA) and spinocerebellar ataxia tion found in patients with long QT syndrome is a single type 1 and 3 (SCA1 and SCA3). DNAJD1 overexpression amino acid change in the leucine Zipper that serves as decreased ataxin-1 aggregation in HeLa cells. See Cum interaction surface with yotiao. The mutation abolishes mings et al., Nat. Genet., 19(2): 148-152 (1998). Another KCNQ1 binding of yotiao and renders the channel insensi potential cause of neurodegenerative disease is astrocyte tive to cAMP signaling. Recent evidence indicates that injury occurring as a result of CNS trauma and ischemia. yotiao not only provides recruitment sites for KCNO1 Astrocytes are glial cells which respond upon injury to the regulators, but also serves as a signaling sensor of the brain. Injury to these cells is associated with neurodegen phosphorylation state of the channel Subunit. See Saucerman erative diseases such as Alzheimer's as well as psychiatric et al., Circ Res., 95(12): 1216-24 (2004). Thus, SNPs asso disorders such as Schizophrenia and depression. Overexpres ciated with AKAP9 mRNA expression are useful to detect or sion of DNAJD1 resulted in a significant reduction of predict Susceptibility to heart disease and associated disor astrocyte injury. See Qiao et al., J. Cereb. Blood Flow ders, especially arrhythmia, long QT syndrome, Ventricular Metab., 23 (10): 1113-6. This suggests a potential mechanism fibrillation, cardiac arrest and sudden death. by which SNPs associated with DNAJD1 levels are useful as 0151. DNAJD1 is a member of a highly conserved family markers to predict or detect patient Susceptibility to neuro of heat shock proteins (“Hisp'') containing four distinct degenerative disease such as neurodegeneration, Alzhe domains including a 70-amino acid residue referred to as the imer's disease, Parkinson's disease, Huntington's disease, DNAJ domain. This domain is necessary in forming an prion disorders, DRPLA, SCA1, SCA3, schizophrenia and interaction between DJAJD1 and interacting proteins. See depression as well as to predict the progression of or ability Kelley, W. L., Trends Biochem. Sci., 23:222-227 (1998). to recover from Such diseases. Specifically, DNAJD1 is a member of the Hsp40 heat shock 0154 Ischemia results from oxygen deprivation in tissues protein family, a set of chaperone proteins, which partici usually due to lack of blood flow. There is evidence that pates in protein folding and regulation of diverse cellular DNAJD1 may provide protection against injury caused by processes including protein transport, cell cycle and stress ischemia Such as brain, myocardial and intestinal injury. See responses. DNAJD1 functions in concert with Hsp70 family Qiao et al., J. Cereb. Blood Flow Metab., 23(10): 1113-6. As members to assist in protein folding and prevention of such, SNPs associated with mRNA levels of DNAJD1 can protein misfolding. See Hendrick, J. P. and Hartl, F. U. be useful to predict or detect ischemia and ischemic-type FASEB.J., 9, 1559-1569 (1995) and Hartl, F.U., Nature, 381, injury, especially cardiomyopathy, coronary disease, coro 571-579 (1996). For example, DNAJD1 and DNAJA2 par nary artery disease, heart attack, stroke, and intestinal ticipate in mitochondrial protein import and DNAJA4 is ischemia. They are also useful as a means of prognosis and involved in heat stress response. progression of Such injury. 0152 DNAJD1 was cloned by differential display PCR 0.155 GOLPH4 is a ubiquitously expressed, type II mem from ovarian epithelial cells and named methylation-con brane protein that resides in the cis-Golgi. This human trolled J protein, MCJ. Analysis by RT-PCR has shown that protein contains a short, cytoplasmic tail of twelve amino two-thirds of primary ovarian tumors have either a complete acids and a large lumenal domain of 664 residues. See loss or decreased expression levels of MCJ. See Shridhar et Natarajan et al., Mol. Biol. Cell, 15(11): 4798-806 (2004); al., Cancer Research, 61:4258-65 (2001). DNA methylation Linstedt et al., Mol. Biol. Cell, 8(6): 1073-87 (1997). The has been shown to inactivate tumor Suppressor genes and is outer region of the lumenal domain is very acidic because it increasingly being viewed as a tumor risk marker in non is enriched in acidic amino acids. See Natarajan et al., Mol. cancerous tissues. See Malfoy, B., J. Cell Sci., 113 (Pt Biol. Cell, 15(11): 4798-806 (2004). The region of GOLPH4 US 2007/0O82347 A1 Apr. 12, 2007

closest to the membrane contains elements that facilitate its rate-limiting step in vesicle fusion. Trafficking pathways pH sensitive targeting. See Natarajan et al., Mol. Biol. Cell, dependent on rabpatin-5 include homotypic fusion of endo 15(11): 4798-806 (2004); Bachert et al., Mol. Biol. Cell, somes, transport from the trans-Golgi network (TGN) to the 12(10):3152-60 (2002). When treated with an agent that endoSome and recycling of membranes from the early prevents acidification, GOLPH4 moves to endosomes. Upon endosome to the Golgi complex. See Stenmarket al., Cell, removal of such an agent, GOLPH4 redistributes to the 83(3):423-32 (1995). cis-Golgi. See Puri et al., Traffic 3(9):641-53 (2002). 0159 Rabaptin-5 binds both the small GTPase Rab5 as GOLPH4 is also known as GPP130 because it is 130-kDa in well as the Rab5 GTP exchange factor (GEF) Rabex-5. size. Linstedt et al., Mol. Biol. Cell, 8(6): 1073-87 (1997). Rabex-5 promotes the exchange of GDP for GTP on Rab5 0156 GOLPH4 seems to play an important role in the thereby catalyzing the formation of active Rab5-GTP on movement of proteins and toxins from endoSomes to the membranes and increasing the affinity of Rab5 for Rabaptin Golgi via the bypass pathway. Studies on Shigella toxin B 5. These interactions are thought to promote endosome subunit trafficking revealed that the bypass pathway fusion. See Mattera et al., EMBO, 22(1):78-88 (2003). bypasses the conventional route, the late endoSome/pre Inhibition of vesicle production was shown to occur upon lysosome pathway. The bypass pathway transports proteins depletion of RABEP1/Rabex-5 complex. This further sug or toxins directly from early endosomes to the Golgi and it gests the role of RABEP1 in vesicle recycling. See Pagano is branched out of the plasma membrane receptor re-cycling et al., Mol. Biol. Cell, 15(11):4990-5000 (2004). route. Early sorting may be advantageous in that it may 0.160 The N-terminus of Rabaptin-5 contains a binding reduce the amount of degradation incurred by proteins or site for the Small GTPase Rab4. The GTPase Rab4 is a toxins that cycle between the Golgi and plasma membrane. marker for early endoSomes and regulates recycling of In the study, GOLPH4 silencing by RNAi disrupted the membrane to the Golgi complex. An adjacent GAE binding normal movement of proteins and toxins. Two proteins site interacts with Y1-adaptin, a Subunit of the adaptor dependant on the bypass pathway accumulated in the early/ complex 1 (API). The AP-1 complex mediates transport recycling endosomes. Shiga toxin B movement was also from the endosome to the Golgi. Adaptor protein complexes inhibited. Yet, proteins known to travel via the late endo are hetero-tetramers that integrate cargo selection with the some pathway continued to travel to the Golgi. See Natara formation of clathrin-coated vesicles. By binding both Rab4 jan et al., Mol. Biol. Cell, 15(11): 4798-806 (2004). and Y1-adaptin, Rabaptin-5 regulates endosome-to-Golgi O157 Thus, GOLPH4 affects the functionality of a nor transport. See Deneka et al., EMBO, 22(11):2645-2657 mal retrieval route for proteins and Shiga B toxin to the (2003). Defects in endosomal trafficking have been associ Golgi. It may also determine the viability of invasion by ated with neurodegenerative diseases such as Alzheimer's other toxins, since bacterial and plant toxins are taken up by disease and Niemann-Pick type C disease. cells through endocytosis and then exert their effect in the cytoplasm. See Natarajan et al., Mol. Biol. Cell, 15(11): 0.161 Specifically, defects in synaptic vesicle recycling 4798-806 (2004). Polymorphisms that correlate with expres such as those associated with RABEP1 may be involved in sion levels of GOLPH4 may be used to predict human synapse loss common in Alzheimer's disease. See Yao et al., Susceptibility to diseases that occur as a result of the Neurosci. Lett., 252(1):33-36 (1998). Accumulation and non-movement of proteins to the Golgi due to low levels or formation of beta-amyloid plaques in brain tissue is a an absence of GOLPH4. Absence of or low levels of hallmark of Alzheimer's disease pathology. Recently, high expression of GOLPH4 may also predict conditions caused levels of RABEP1 interacting protein Rab5 were demon by premature direction of components in the endocytosis strated to be highly enriched with beta-amyloid precursor pathway towards the endosomal degradation pathway. protein APP. See Ikin et al., J. Biol. Chem., 271 (50):31783-6 Finally, polymorphisms that correlate with normal or (1996). increased expression levels of GOLPH4 may predict human 0162 Receptor tyrosine kinases (RTK) are transmem susceptibility to bacterial toxins. brane proteins that transduce extracellular signals to the cytoplasm and initiate a variety of cell responses through 0158 RABEP1 is a 100-kD protein that regulates endo phosphorylation cascades. An extracellular domain receives Some trafficking by providing a tether between transport activating signals through specific ligands inducing receptor vesicles and target membranes. The RABEP1 protein inter multimerization. The intracellular domain of RTKs contains acts with Rab5, a regulator of endocytic vesicle trafficking. a tyrosine kinase activity which, upon ligand binding, auto As with other Ras protein family members, Rab5 recruits phosphorylates the receptor dimer. The phosphorylated form RABEP1 to the early endosome. Trafficking pathways of the receptor recruits accessory proteins that propagate the involving RABEP1 include homotypic fusion of endosomes, signal through Subsequenct phosphorylation/dephosphory transport from the trans-Golgi network to the endosome and lation events resulting in activation of growth-promoting or recycling of membranes from the early endsome to the growth-inhibiting genes. RTK signaling is abrogated by Golgi. Overexpression of RABEP1 was shown to cause morphological alterations to the early endoSome similar to internalization of the receptor through endocytosis. those caused by the overexpression of interacting protein 0.163 Upregulation of RTKs is a frequent event in tumor Rab5. Further, immunodepletion of RABEP1 causes a sig formation and metastasis. Transforming mutations lead to nificant decline of early endosome fusion regulated by Rab5. permanent or increased activation of the receptor by gene The central role of RABEP1 is to provide a tether between fusion events resulting in overexpression, mutations causing vesicles and target membranes prior to vesicle fusion allow ligand-independent activation or mutations activating the ing SNAREs and other membrane and vesicle proteins to kinase domain. Disruptions in receptor endocytosis and establish contact and determine vesicle-target membrane recycling are another process that can affect the level of specificity. RABEP1 mediated “docking of vesicles is a effective receptor activity on the cell surface. Rab5 has been US 2007/0O82347 A1 Apr. 12, 2007

shown to contribute to EGFR recycling and changes in Rab5 diabetes mellitus and rheumatoid arthritis. One example of expression levels modulate the amount of EGFR present on Such an autoimmune response is the recognition and destruc the cell membrane. See Dinneen et al., Exp. Cell Res., tion of cells lacking HLA class I proteins by natural killer 294(2):509-22 (2004). Expression levels of Rabaptin-5 (NK) cells. Impaired HLA class I expression increases could equally modify the availability of EGFR and other susceptibility to autoimmune disease caused by NK cell receptor kinases thereby affecting cancer cell growth and mediated cytotoxicity. HLA class I proteins are synthesized differentiation. from proteins imported into the ER lumen by the TAP 0164. TAP has an ATP-binding cassette and translocates complex and show diminished expression in individuals peptides from the cytosol to the lumen of the endoplasmic with TAP2 deficiency. See Vitale et al., Blood, 99(5):1723 reticuclum (ER) where antigen presenting MHC class I 1729 (2002). Underexpression of TAP2 leads to autoimmu molecules bind. ATP is hydrolyzed by TAP to facilitate the nity caused by lack of HLA class I proteins. peptide transport process. The TAP complex is composed of two polypeptide subunits, TAP1 and TAP2. These proteins 0168 NARG2 is expressed in fetal tissue, but is signifi are similar in structure, each containing a transmembrane cantly down-regulated in adults with the most Substantial domain and a nucleotide binding domain. See Chen et al., J. expression levels found in the kidney, testes, liver and brain. Biol. Chem., 279(44):46073-46081 (2004). The TAP2 sub Down-regulation of NARG2 was shown to be disrupted in unit was shown to form the pore of the TAP complex the absence of NMDA receptor in NMDAR1 knockout demonstrating its essential role in mediating peptide load mice. Intermediate levels of NARG2 were present in NMDAR1+/- mutants. Further, P19 culture cells treated ing. TAP2 is also required for recruitment of tapasin with retinoic acid to induce neuronal differentiation caused polypeptide, another necessary component in TAP-mediated a decline in NARG2 expression levels concurrent with protein translocation. See Koch et al., J. Biol. Chem., increased NMDAR1 expression levels. See Sugiura et al., 27(11): 10142-10147 (2004). Eur: J. Biochem., 271 (23-24):4629-37 (2004). These studies 0165 Surface expression of class I major histocompat demonstrate a correlation between NARG2 expression lev ibility complex (MHC class I) is critical in the ability of the els and neuronal differentiation, mainly the transition of immune system to recognize and eliminate mutated and neuronal precursor cells to neurons. infected cells. MHC class I proteins synthesized in the ER are expressed on cell Surfaces. Foreign peptides resulting 0169. The inability of the mammalian CNS to regenerate from malignancy (e.g. cancer cells) or viral infection are after damage has been implicated in a number of neurode presented on the MHC class I protein triggering immune generative diseases Such as amyotrophic lateral sclerosis response. Viral pathogens have evolved by developing (ALS), Parkinson's disease, Alzheimer's disease and other methods of evading immune system detection and response. types of brain and spinal cord injury. See Chen et al., Proc. For example, herpes-simplex virus (HSV) escapes immune Natl. Acad. Sci. USA., 101(46):16357-62 (2004). Stimula recognition through downregulation of MHC class I Surface tion by agents that induce neuronal differentiation creates a expression. See Lankat-Buttgereit, B. and Tampe, R., source of regenerative cells with a therapeutic effect in the Physiol. Rev., 82(1):187-204 (2002). The demonstrated abil treatment of Such neurodegenerative diseases. See Richar ity of HSV protein ICP47 inhibits the TAP complex thereby son et al., Brain Res., 1032(1-2): 11-22 (2005). Thus, the preventing production and presentation of MHC class I SNPs of the present invention are useful to predict or detect antigens. See Ahnet al., EMBO.J., 15(13):3247-3255 (1996) Susceptibility to neurodegenerative diseases in an individual and Kyritsis et al., J. Biol. Chem., 276(51):48031-9 (2001). as well as to predict progression of these diseases. Thus, a decline in TAP2 levels leading to decreased MHC 0170 NMDA receptors have been studied extensively. class I presentation would result in impaired immune NMDA receptors are known mediate synaptic transmission response and increased Susceptibility to viral infection in an and neural plasticity in the mammalian central nervous individual. system. (See, Monaghan Annu Rev Pharmacol Toxicol, 0166 Cancer cells lack the ability to present cell surface 29:365-402 (1989); Collingridge Pharmacol Rev. 41: 143 antigens. Several cancers, such as melanomas, exhibit of 210 (1989); McBain Physiol Rev. 74:723-60 (1994)). decreased levels of MHC class I surface presenting proteins. NMDA receptors are differentially expressed during devel See Sherman et al., Crit. Rev. Immunol., 18(1):47-54 (1998). opment (Sheng Nature, 368:144-7 (1994)). NMDA recep Diminished TAP2 expression levels are present in breast tors are involved in a variety of fundamental biological cancer and human non-Small cell lung cancer cells. See processes including brain development by stabilizing con Alimonti et al., Nature Biotechnol., 18(1):515-520 (2000) verging synapses (Scheetz FasebJ, 8:745-52 (1994)), stimu and Seliger et al., Immunol. Today, 18(1):292-299 (1997). lating cerebellar granule cell migration (Hitoshi et al., Sci TAP complex downregulation has also been shown to cause ence, 260:95-97 (1993); Farrant Nature, 368:335-9 (1994): HLA class I antigen loss. See Chen et al., Nat. Genet., Rossi Neuropharmacology, 32:1239-48 (1993)) and devel 13(1):210-213 (1996). Decreased TAP2 expression would opment (Burgoyne J Neurocytol, 22:689-95 (1993)), induc lead to a decline in MHC class I and HLA class I molecules ing long term depression (Battistin Eurj Neurosci, 6:1750-5 necessary for cancer cell recognition and elimination. Thus, (1994); Komatsu Neuroreport, 4:907-10 (1993); Tsumoto TAP2 expression levels are indicative of cancer cell pres Jpn. J. Physiol., 40:573-93 (1990)) and apoptosis (Finiels J ence as well as potential to metastasize. Neurochem, 65:1027-34 (1995); Ankarcrona FEBS Lett, 394:321-4 (1996)). NMDA receptors are also known con 0167 Occasionally, the immune system attacks endog tribute to excitatory cell death in a number of adult patho enous self-proteins which it mistakes as foreign pathogens. logical conditions (Greenamyre Neurobiol Aging, 10:593 This process, known as autoimmunity, can result in diseases 602 (1989); Meldrum Trends Pharmacol Sci, 11, (1990) Such as Wegener's granulomatosis, multiple Sclerosis, type 1 379-87; Clark, S, “The NMDA receptor in epilepsy, 2 edin. US 2007/0O82347 A1 Apr. 12, 2007

Oxford University Press, Oxford, 1994, 395-427 pp.; Doble, 0173 References which disclose other NMDA receptor A., Therapie, 50:319-37 (1995)). blockers as well as assays for identifying an agent that acts as Such a blocker and toxicity studies for pharmacologic 0171 Excitatory amino acid receptors, including NMDA profiles are disclosed in the foregoing and following articles receptors, are known to be involved in neurodegenerative which are all hereby incorporated by reference in their diseases, and specific NMDA antagonists are being used in entirety. (See also Jia-He Li, et al., J Med Chem 38:1955 clinical research (Lipton Trends Neurosci, 16:527-32 1965 (1995); Steinberg et al., Neurosci Lett, 133:225-8 (1993)) for the potential treatment of stroke, CNS trauma (1991); Meldrum et al., Trends Pharmacol Sci, 11:379-87 (Faden Trends Pharmacol Sci, 13:29-35 (1992)), epilepsy (1990); Willetts et al., Trends Pharmacol Sci, 11:423-8 (Thomas J Am Geriatr Soc, 43:1279-89 (1995); Perucca (1990); Faden et al., Trends Pharmacol Sci, 13:29-35 Pharmacol Res, 28:89-106 (1993)), pain (Elliott Neuropsy (1992); Rogawski, Trends Pharmacol Sci, 14:325-31 chopharmacology, 13:347-56 (1995)), Huntington's disease (1993); Albers et al. Clinical Neuropharm, 15:509-514 (Purdon J Psychiatry Neurosci, 19:359-67 (1994)), AIDS (1992); Wolfe et al., Am J Emerg Med 13:174-6 (1995); dementia (Lipton Dev Neurosci, 16:145-51 (1994); Lipton Bigge, Biochem Pharmacol, 45:1547-61 (1993)). Examples Ann N Y Acad Sci, 747:205-24 (1994)), and Alzheimer's of known NMDA receptor antagonists include memantine, adamantane, amantadine, an adamantane derivative, dex disease (Barry Arch Phys Med Rehabil, 72:1095-101 (1991)) tromethorphan, dextrorphan, dizocilpine, ibogaine, ket and Parkinson's disease (Ossowska N Neural Transm Park amine, remacemide, and phencyclidine. The SNPs in Dis Dement Sect, 8:39-71 (1994)) (Rogawski Trends Phar NARG2 useful in predicting NARG2 gene expression can macol Sci, 14:325-31 (1993)). In vivo treatment with some also be used in predicting the gene expression of NMDAR1, of these agents manifest PCP-like psychotomimetic effects. because of the inverse correlation between NARG2 expres Hence, research has been underway to discover and develop sion and NMDAR1 expression. more therapeutically useful and less toxic drugs (Willetts Trends Pharmacol Sci, 11:423-8 (1990)). One less-toxic 0.174 RNA helicases of the DEAD box family are present NMDA antagonist candidate is Ro-01-6794/706 or dextror in almost all organisms and function in a variety of RNA phan (Ann N Y Acad Sci, 765 249-61, 298 (1995)). Dex metabolism related processes. RNA metabolism involves a tromethorphan and its metabloite dextrorphan are widely dynamic rearrangement of RNA and proteins during tran used over the counter as antitussives (Irwin Drugs, 46:80-91 Scription, pre-mRNA splicing, translation initiation, RNA (1993)) which are NMDA channel blockers (Fekany Eur J transport and RNA degradation. Single-stranded RNA is Pharmacol, 151:151-4 (1988); ChoiJ Pharmacol Exp Ther also prone to form partial intra- and intermolecular interac 242:713-20 (1987)) that may be a clinically useful neuro tions, which might interfere with or regulate some of the protectant (Steinberg Neurosci Lett 133:225-8 (1991)). above processes. DEAD box RNA helicases unwind RNA Therapeutically tolerated doses of roughly 30 mg (q.i.d.) double strands and dissociate RNA-protein complexes. The orally are used for the over the counter antitussive action, ATPase component of the DEAD box motif provides the and to 90 mg (q.i.d.) orally for clinical treatment of brain energy required for unwinding RNA duplexes, rearranging ischemia (Albers Clin. Neuropharmacol., 15:509-14 RNA secondary structure or regrouping RNA-protein inter (1992)). Side effects at high doses of dextromethorphan and actions. See Imaizumi, et al., Biochem. Biophys. Res. Com dextrorphan included drowsiness, nausea, and decreased mun., 292(1):274-9 (2002). coordination. Toxic high doses of dextromethorphan and 0.175 Innate immune response is an organism's first-line dextrorphan have been described (Wolfe Am J Emerg Med, defense against pathogens in advance of the Subsequent 13:174-6 (1995); Hinsberger J Psychiatry Neurosci, process of adaptive immunity. One essential component of 19:375-7 (1994)); Loscher Eur J Pharmacol, 238:191-200 innate immune response are cytokines of the type I inter (1993)). feron family which are induced by bacterial molecules such as lipopolysaccharide (LPS) and CpG DNA, and viral infec 0172) Numerous potentially clinically useful NMDA tion. Signaling by pathogen associated molecular patterns antagonists have been studied (Jane "Agonists and competi (PAMPs) is received by members of the Toll-like receptor tive antagonists: structure-activity and molecular modeling (TLRs) family. Extracellular double-stranded RNA, LPS, studies’, 2 edin., Oxford University Press, Oxford, 1994, viral single-stranded RNA and CpG DNA are recognized by 31-104 pp: Andaloro Society for Neuroscience Abstracts, TLR3, TLR4, TLR8 and TLR9, respectively. Ligand binding 604 (1996); Bigge Biochem Pharmacol, 45:1547-61 (1993); at the extracellular, leucine-rich repeats induces recruitment Ornstein, P., “The development of novel competitive N-me of adaptor molecules such as MyD88, IRAK, TRAF6 and thyl-D-aspartate antagonists as useful therapeutic agents: Trif to the cytoplasmic domain. This initiates a signaling Discovery of LY274614 and LY233536, Raven Press, New cascade that ends with the activation of transcription factors, York, 1991, 415-423 pp), and some are even orally avail among them IRF3 and NFkB, and the activation of a able, including some derivatives EAB-515 (Li J Med Chem, pro-inflammatory transcriptional program. See Yoneyama, 38 1955-65 (1995); Lowe Neurochem Int, 25:583-600 (1994)), memantine (Parsons Neuropharmacology, 34:1239 et al., Nature Immunology, 5(7):730–737 (2004). 58 (1995); Kornhuber J Neural Transm Suppl. 43:91-104 0176) During infection RNA viruses enter the cell (1994); Wenk Eur J Pharmacol, 293 267-70 (1995)), and through membrane fusion, delivering their RNA genome in ketamine (Parsons Neuropharmacology, 34:1239-58 (1995); form of a RNP particle to the cytoplasm and bypassing both Sagratella Pharmacol Res, 32:1-13 (1995); Porter J Neuro the extracellular TLR3 as well as TLR3 molecules in the chem, 64:614-23 (1995)). Some of these NMDA antagonists endocytotic pathways. The cytoplasmic sensor for double are approved for use, several others are in clinical trials for stranded RNA is the RNA helicase DDX58, also known as the treatment of neurodegenerative disease, epilepsy, stroke, RIG-1. See Li, et al., J. Biol. Chem., 280(17): 16739-47 and other diseases. (2005). The protein not only contains a RNA helicase motif, US 2007/0O82347 A1 Apr. 12, 2007

but also two N-terminal death-like domains, which are transmembrane protein with two TM domains, one located related to the protein-protein interaction domains DED and N-terminally and a second one at the C-terminus. This CARD. These domains promote homotypic interactions and topology creates two intracellular domains at the N- and serve as platforms for the assembly of signaling complexes. C-termini and a large extracellular loop located between the It has recently been shown that RIG-1 regulates dsRNA TM domains. CD39 appears to be constitutively palmitoy induced signaling and is essential for induction of IRF3 after lated at Cys 13 and this fatty acid modification promotes viral infection. The RNA helicase domain is required for targeting to calveolae, plasmamembrane regions enriched in response to viral infection and appears to negatively regulate signaling molecules including purinergic receptors. Accord the CARD domain in the absence of double-stranded RNA. ing to data from CD39 deficient mice CD39 is the main The CARD-like domain of RIG-1 constitutively activates ecto-nucleosidase at the inner vascular surface. CD39 con IRF3 and NFkB when expressed in mouse L929 cells. verts ATP to ADP and qADP to AMP. AMP is catabolized by Abrogation of RIG-1 by RNAi impairs activation of IRF3 in ecto-5'-nucleotidase to adenosine. By promoting the degra response to viral infection and over-expression of RIG-1 dation of ADP to adenosine CD39 is a critical regulatory reduces viral yield. RIG-1/DDX58 thus is a crucial compo molecule for maintaining blood flow. See Koziak et al., J. nent of the innate immune response and levels of RIG-1 Biol. Chem., 275(3):2057-62 (2000). could predict individual variation in immune response to 0180 CD39 knockout mice exhibited longer bleeding viruses. See Yoneyama, et al., Nature Immunology, times and defects in platelet aggregation despite little 5(7):730–737 (2004). Overexpression of RIG-1 has also changes in platelet numbers, plasma ATP or ADP concen been shown to increase ISGI5 levels resulting in an increase trations. Instead disrupted thromboregulation was due to in natural killer cells and cytotoxicity. See Cui, et al., desensitization of purinergic receptors that could be recon Biochem. Cell Bio., 82(3):401-5 (2004). Furthermore, stituted by exposure to exogenous ATPDases. CD39-/- silencing of RIGI expression impaired response to Sendai endothelial cells failed to abrogate platelet aggregation after virus in hepatocytes. See Li, et al., J. Biochem., stimulation with ADP Increased susceptibility of CD39 280(17): 16739-47 (2005). negative mice to vascular injury was suggested by increased 0177 COX2 overexpression has been linked to carcino deposition of fibrin in most vasculatures, including pulmo genesis and tumorigenesis. Specifically, COX2 expression is nary, cardiac, renal, cerebral and splenic. CD39-null mice Sufficient to induce mammary gland tumorigenesis. See Lui. showed impaired chemotactic response of macrophages and et al., J. Biol. Chem. 276: 18563-18569 (2001). Overexpres monocytes and absence of new vessel growth. See sion of COX2 was also shown to be an early, central event Mizumoto et al., Nature Medicine, 8(4):358-365 (2002). in carcinogenesis in Apc(delta-716) knockout mice. See 0181 Transgenic expression of CD39 in mice also results Oshima, et al., Cell 87: 803-809 (1996). RIGI overexpres in increased bleeding times and disruption of platelet aggre sion lead to increased expression of COX2 mRNA in gation. However, CD39 transgenic mice are protected bladder cancer cells and further induces COX2 activity in against Systemic thrombosis when challenged with collagen endothelial cells. This demonstrates the potential role of or ADP. See Eniyoji et al., Nature Medicine, 5(9):1010-1017 RIGI expression levels in the role of cancer development (1999). Increased expression of CD39 has also been related and tumor progression. See Imaizumi, et al., Biochem. to plaque stability and reduced thrombus formation in Biophys. Res. Commun., 292(1):274-9 (2002). angina pectoris patients suggesting a role in prevention of 0178 Vascular injury, shear stress, hypoxic conditions acute coronary syndromes. See Hatakeyama et al., Am. J. and inflammatory mediators induce the release of adenosine Cardiol. 95(5):632-5 (2005). nucleotides into the local intracellular vasculature. ATP and 0182 Acute rejection of allograft transplants has been ADP are also present in extracellular fluid due to plasma reduced through the application of immuno-Suppressants. A membrane permeability and exocytotic vesicles. In blood critical feature is inflammatory response that triggers platelet ATP and ADP regulate platelet aggregation through binding deposition and small vessel thrombosis. CD39 expression to purinergic P2 receptors on the platelet surface. Free ADP levels appear to correlate with rejection risk. Xenografts is a potent activator of platelet aggregation, while ATP acts from CD39 deficient mice had higher rejection rates while as a competitive antagonist. ATP also acts as an anti grafts from CD39 transgenic mice showed increased sur thrombotic through activation of two inhibitors of platelet vival times. See Imai et al., Mol. Med., 5(11): 743-52 (1999). aggregation, prostacyclin (PGI2) and nitric oxide (NO). 0183 Langerhans cells (LC) are dendritic cells within the Both PGI2 and NO improve blood flow by relaxing smooth epidermis that contribute to T cell stimulation and inflam muscles and promoting vasodilation as well as inhibiting mation by presenting antigens for T cell responses. In CD39 local effects of ADP on platelet activation. The breakdown deficient cells ecto-nucleosidase activity is absent in Langer product of AMP adenosine, is also an anti-thrombotic with hans cells indicating that ENTPD1 is the main ecto-nucle actions on platelet aggregation that oppose those of ADP. osidase in LC cells. In CD39-/- mice inflammatory See Burnstock, G., and Williams, M., J. Pharmacol. Exp. responses to skin irritants were increased. Pro-inflammatory Then, 295(3):862-9 (2000). mediators ATP and ADP released by keratinocytes contrib 0179 Extracellular ATP and ADP are hydrolyzed by ute to the activation of T cells, which trigger a second set of ecto-nucleoside triphosphate diphosphohydrolases (ENTP ATP dependent signaling events between T cells and den Dases), nucleotide pyrophosphatase/phospho-diesterase I dritic cells. The level of ATP appears to be critical in family members and alkaline phosphatases. Members of all determining the severity of the response and the expression three families are present in plasma. The main ecto-nucle level of CD39, responsible for ATP hydrolysis, could reflect osidase in vascular endothelial cells responsible for the the inter-individual variability in inflammatory response to hydrolysis of ADP is CD39, which recognizes all forms of irritants and immunogens. See Mizumoto et al., Nature nucleoside triphosphates that occur physiologically. It is a Medicine, 8(4):358-365 (2002). US 2007/0O82347 A1 Apr. 12, 2007

0184 FKBP1a is the major binding protein for macrollide lated by phosphorylation, either directly or via phosphory immunosuppressant drugs including FK506 and rapamycin. lation of accessory proteins. See Marx, et al., Cell, The FK506/FKBP1a complex binds to and inhibits the Ca2+ 101(4):365-76 (2000). dependent phosphatase calcineurin. Calcineurin is a central regulator of T cell activation by dephosphorylating the 0188 The RYR2 homo-tetramer forms a complex with transcription factor NFAT which regulates expression of FKBP12.6, calmodulin, protein kinase A, protein phos several cytokines. The rapamycin/FKBP1 a complex acts phatase 1 and protein phosphatase 2A. Binding of through a different pathway by inhibiting the serine-threo FKBP12.6 stabilizes the closed form of the channel. Hyper nine kinase mTOR resulting in cell cycle arrest in G1 phase. phosphorylation of RYR2 as observed in heart failure, Both actions are the basis for the use of FK506 type results in dissociation of FKBP12.6 from RyR2, destabili immunosuppressants in transplantation Surgery. The FKBP zation of the closed state and Ca' leaks during diastole. gene family has been shown to be associated with antitumor Since FKBP12.6 promotes coupling between RYR2 recep activities. Particularly, FKBP1 a gene expression has been tors, loss of FKBP12.6 also disrupts the simultaneous sys shown to have antitumor effects through binding rapamycin, tolic opening and diastolic closing of RYR2s. Both the thereby arresting cells in G1. It was also noted that antitu reduced Ca' concentration in the SR and the uncoupling morogenic effects could be related to the stimulation of T of RYR2 function contribute to cardiac arrhythmia. cell function by FKBP1a. The cell cycle inhibitory function 0189 The Ca' ATPase SERCA2 is regulated by the of the rapamycin/FKBP1a interaction has led to applications accessory protein phospholamban (PLN). PLN in its of rapamycin as an anti-proliferative agent in cancer therapy. unphosphorylated state inhibits SERCA2 activity. Calcium See Fong et al., PNAS, 100(24): 14253-14258 (2003). release via RYR2 activates CAMKII, which phosphorylates PLN and relieves SERCA2 inhibition. This promotes car 0185. FKBP1a expression levels have been shown to diac contractility by recharging the SR calcium stores for the increase in the case of nerve damage. Particularly, FKBP1a next cycle of release. In failing hearts a chronically activated is upregulated Subsequent to nerve crush injury. See Sezen God-coupled receptor System activates protein kinase C et al., Int. J. Impot. Res., 14(6):506-12 (2002). Regenerating which phosphorylates inhibitor-1, thus abrogating down neurons identified by retrograde labelling were found to regulation of protein phosphatase 1 (PP1). PP1 induced have upregulated FKBP1a mRNA levels. See Mason et al., hypophosphorylation of PLN diminishes the activity of Exp. Neurol., 181 (2):181-9 (2003). SERCA2 and prevents proper calcium recycling. Dysfunc 0186 Calcium binding proteins of the penta-EF family tion in the calcium cycling process triggers compensatory (PEF) contain a conserved helix-loop-helix signature that mechanisms in the heart, including hypertrophy, remodeling coordinates an Ca' ion in a pentagonal bipyramidal con and apoptosis. The critical role of calcium in regulating figuration using the oxygen atoms of an invariant glutamate cardiac contractility has made calcium-binding proteins a or aspartate for ligand binding. PEF proteins include Sorcin, new interest for drug-based interference in heart failure. grancalcin, peflin, calpain and ALG-2. PEF family members contain five repetitive EF-hand motifs, dimerize through 0.190 Sorcin has been found complexed to three different unpaired C-terminal EFs and can also form heterodimers. cardiac calcium channels: the LTCC channel, responsible for An N-terminal hydrophobic domain promotes Ca' depen the initial inward Ca' current, the RYR2 receptor which dent translocation from a soluble Ca' free form to a Ca'" controls release of the Ca' stores from the SR and bound membrane-attached version. See Hansen, et al., FEBS SERCA2 which actively returns Ca' to the SR. The Lett., 545(2-3 :151-4 (2003) and Farrell, et al., Biol. Res., calcium bound form of sorcin inhibits receptor activity. 37(4):609-12 (2004). Sorcin was originally identified as a Phosphorylation of sorcin by PKA results in loss of receptor gene amplified in drug-resistant cancer cells. Its chromo inhibition. Transgenic mice over-expressing Sorcin in heart somal location is close to that of ABCB1 (MDR1), a gene muscle cells lack obvious signs of cardiomyopathy, but frequently found amplified in response to chemotherapy. show defects in cardiac contractility. Sorcin protein prefer entially localizes to the Z-lines that contain high concentra Widely expressed in many tissues sorcin co-localizes with tions of both the LTCC and RYR2 channels. This co NMDA receptors in brain and is found near T-tubules in localization is disrupted in myocytes from a rat model of heart muscle. Several interactors for sorcin have been iden heart failure. Binding of sorcin to RYR2 decreases specifi tified, including annexin VII and presenilin 2, both Suggest cally the inward Ca' current triggered activity of RYR2, ing a role for Sorcin in regulation of calcium homeostasis. thereby diminishing the excitation-contraction coupling. See Meyers, et al., J. Biol. Chem., 278(31):28865-71 (2003). Overexpression of Sorcin in rat cardiomyocytes also affects 0187 Best described is its involvement in the regulation the Ca' uptake and Ca' load in the sarcoplasmic reticu of excitation-contraction coupling in the heart muscle. Con lum, indicating activation of the Ca' ATPase. This activity traction of the heart muscle depends on coordinated intra is reduced in failing hearts, which show increased PKA cellular calcium cycling. It is initiated by the influx of a dependent phosphorylation of Sorcin. Since Sorcin is regu small Ca' current through the voltage-activated LTCC lated by phosphorylation through the same set of enzymes as channel (L type Ca' channel) during membrane depolar several other components of the cardiac calcium cycle ization. This triggers a much larger release of calcium from (PKA, PP1), it does functionally resemble the two previous the sarcoplasmatic reticulum (SR) through the calcium described accessory proteins. See Matsumoto, et al., Basic release channel of the SR, the ryanodine receptor RYR2. Res. Cardiol. (2005) and Meyers, et al., J. Biol. Chem., Calcium binds to tropomyosin C in the myofilaments stimu 278(31):28865-71 (2003). Consistent with this, sorcin over lating contraction. Dissociation of calcium from tropomyo expression has been associated with an increase in cardiac sin begins relaxation and free calcium is returned through contractility and the rescue of abnormal contractile function efflux pumps like the Cat ATPase in the SR and the in the diabetic heart. See Suarez, et al., Am. J. Physiol. Heart Na-CA2") exchanger. Each of these transporters is regu Circ. Physiol., 286(1):H68-75 (2004). Recently, Sorcin US 2007/0O82347 A1 Apr. 12, 2007 20 overexpression was demonstrated to improve cardiac con proteins in response to viral infection. IFNA is produced by tractility in vivo in transfected rat hearts. See Frank, et al., cells in response to viral infection. Defects in IFNA pro J. Mol. Cell. Cardiol., 38(4):607-15 (2005). The level of duction were found in 30 children with recurrent respiratory sorcin expression could thus affect susceptibility to heart infection. See Isaacs et al., Lancet II, 950-952 (1981). failure and contribute to variability in response to medica Overexpression of IRF5 induces IFNA gene expression, tion targeting cardiac contractility. underlining the importance of IRF5 levels in immune system 0191 Sorcin expression levels were measured in leuke response. Viral infection induces phosphorylation of IRF5 mic blast cells of patients with acute myloid leukemia and increases binding to the virus regulatory element. See (AML). Poor patient prognosis was associated with Sorcin Barnes et al., J. Biol. Chem., 276(26):23382-90 (2001). overexpression and remission rates were shown to be higher 0196) Toll-like receptors (“TLRs) can detect most for in patients with low sorcin expression than those with higher eign microbes and are thus essential for innate recognition of expression. See Tan, et al., Leuk. Res., 27(2): 125-31 (2003). viral pathogens in mammals. See Beutler, B., Nature, Sorcin expression has also been shown to have an effect on 430(6996):257-63 (2004). Reduced TLR induction was cell resistance to chemotherapeutics. Specifically, Sorcin observed in IRF5 deficient mice demonstrating another overexpression via gene transfection in K562 cells resulted association of IRF5 with immune response. See Takaoka et in increased resistance to chemotherapeutics including al., Nature, 434(7030):243-9 (2005). In view of the above, doxorubicin, etoposide, homoharringtonine and Vincristine. IRF5 mRNA expression levels are useful to predict and/or Sorcin expression was also inhibited in these cells resulting detect an individual’s susceptibility to viral infection as well in a reversal of drug resistance. See Zhou, et al., Luek. Res., as the likelihood of post-infection viral progression. (2005). 0197) AMFR is a receptor for autocrine motility factor, 0192 Exposure to environmental radiation is a normal which is a cytokine secreted by tumor cells to promote tumor hazard for all cells and enhanced radiation is used as a major motility and metastasis. AMFR is a 78-KD cell surface modus of cancer treatment. Genetic factors that modulate glycoprotein (gp78) that transduces signals from the mito sensitivity or resistance to radiation have considerable rel genic cytokine AMF regulating cell motility in cell based evance for the development of diagnostics for susceptibility assays and tumor metastasis in vivo. Aside from its seven to cancer and treatment selection in cancer therapy. Irradia transmembrane domains, AMFR contains a RING-H2 motif tion of cells induces multiple cellular responses to radiation and a leucine Zipper. See Shimizu et al., FEBS Lett., stress, including sensing mechanisms for DNA damage, 456:295-300 (1999). Over-expression of AMFR induces a signaling pathways, DNA repair systems and, if necessary, transformed phenotype and produces tumor in nude mice. apoptosis. See Snyder, et al., Cancer Metastasis Rev., 23 (3- See Onishi et al., Clin. Exp. Metastasis, 20(1):51-58 (2003). 4):259-268 (2004). Signaling through AMF/AMFR induces vascular endothelial 0193 Genome-wide expression profiling has identified growth factor receptor FLT1 thereby stimulating cell growth sets of genes that are differentially regulated upon exposure through tyrosine phosphorylation pathways. See Funasaka et to ionizing radiation. As expected they include genes al., Int. J. Cancer, 101:217-23 (2002). Expression levels of involved in cell cycle progression, cell survival, DNA repair AMFR in melanoma cell lines correlates with their potential and growth control. XRRA1 was cloned from a human to metastasize. See Timar et al., Clin. Exp. Metastasis, colorectal tumor cell line, HCT116. Several clones of 19(3):225-232 (2002). Analysis of primary human skin HCT116 with different responses to radiation were isolated. melanoma tumors identified three types: weak, heterogenous XRRA1 was down-regulated in an untreated cell clone and strong expression. Expression levels appeared to corre resistant to radiation. The 559aa long protein is highly late with growth phenotype, strong expression being found conserved among vertebrates. It contains several leucine in tumors with more pronounced vertical growth indicating rich repeats (LLRs), a feature that has been implicated in a more invasive phenotype. See Timar et al., Clin. Exp. protein-protein interactions. The repeat pattern observed in Metastasis, 19(3):225-232 (2002). About 40% of non-small this protein is consistent with a motif found in proteins cell lung cancers express AMFR, with expression being acting as Ran GTPase activating factors (RangAPs). associated with type mainly in adenocarcinoma. Survival XRRA1 is expressed in many tissues with higher levels was significantly worse in patients with AMFR expression. observed in testis, prostate and ovary. The XRRA1 protein The AMFR expression was also associated with VEGF was localized both in the nucleus and the cytoplasm. expression, both indicating worse prognosis. See Kara et al., 0194 The expression pattern of XRRA1 in HCT116 Ann. Thorac. Surg., 71:944-8 (2001). Approx. 30% of thy clones in response to irradiation showed differences depend momas showed expression of AMFR, again expression ing on radiation sensitivity. A resistant clone had lower basal being associated with worse outcome. See Ohta et al., Int. J. levels, but strongly induced XRRA1 within minutes upon Oncol., 17:259-64 (2000). Since the SNPs and haplotypes radiation treatment. Levels then decreased slowly. A clone described here are associated with the expression level of with increased radiation sensitivity had higher basal levels, AMFR, they can be used to predict cancer susceptibility and but failed to induce XRRA1 upon irradiation. Instead levels prognosis in patients. They may also be useful in predicting dropped significantly and only recovered 24 hours post patients’ response to treatment with VEGF-targeting drugs. treatment. See Mesak, et al., BMC Genomics, 4(1):32 (2003). This differential pattern suggests that XRRA1 is 3. Isolated Nucleic Acids involved in the response to radiation and levels of XRRA1 0198 Accordingly, the present invention provides an may be indicative of resistance and/or sensitivity to radia isolated TLK1 nucleic acid containing at least one of the tion. newly discovered nucleotide variants as Summarized in 0.195 IRF5 is a 504 amino acid interferon regulatory Tables 1, 2 and 3. The term “TLK1 nucleic acid is as factor with a critical role in inducing expression of antiviral defined above and means a naturally existing nucleic acid US 2007/0O82347 A1 Apr. 12, 2007

coding for a wild-type or variant or mutant TLK1. The term NOs: 1, 3-10, wherein the cDNA thus produced contains one “TLK1 nucleic acid' is inclusive and may be in the form of or more of the SNPs of the present invention in Tables 1-3, either double-stranded or single-stranded nucleic acids, and such as EX7(a)+63A, EX7(a)+190C, EX11(a).51A and a single Strand can be either of the two complementing EX25(a)855G. strands. The isolated TLK1 nucleic acid can be naturally existing genomic DNA, mRNA or cDNA. Sequences of 0207. The present invention also encompasses an isolated several naturally existing TLK1 c)NAs and proteins are nucleic acid comprising the nucleotide sequence of a region provided in SEQ ID NOs: 1, 2 and 14-17. of a TLK1 genomic DNA or cDNA or mRNA, wherein the region contains one or more nucleotide variants as provided 0199. In yet another embodiment, the isolated TLK1 in Tables 1-3 (e.g., EX7(a)--63A, EX7(a)--190C, EX11(a).51A nucleic acid has a nucleotide sequence encoding TLK1 and EX25(a)855G), or one or more nucleotide variants that protein having an amino acid sequence according to SEQID will give rise to one or more amino acid variants of Table 2, NO:2 but contains one or more amino acid variants of Tables or the complement thereof. Such regions can be isolated and 1-3 (e.g., EX11(a).51G>A). Isolated TLK1 nucleic acids analyzed to efficiently detect the nucleotide variants of the having a nucleotide sequence that is the complement of the present invention. Also, such regions can also be isolated sequence are also encompassed by the present invention. and used as probes or primers in detection of the nucleotide 0200. In yet another embodiment, the isolated TLK1 variants of the present invention and other uses as will be nucleic acid has a nucleotide sequence encoding a TLK1 clear from the descriptions below. protein having an amino acid sequence that is at least 95%, 0208 Thus, in one embodiment, the isolated nucleic acid preferably at least 97% and more preferably at least 99% comprises a contiguous span of at least 12, 15, 17, 18, 19. identical to SEQ ID NO:2 but contains one or more amino 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 50, 70 or 100 acid variants of Tables 1-3 (e.g., EX11(a).51G>A), or the nucleotide residues of a TLK1 nucleic acid, the contiguous complement thereof. span containing one or more nucleotide variants of Tables 0201 In another embodiment, the present invention pro 1-3 (e.g., EX7(a)--63A, EX7(a)--190C, EX11(a).51A and vides an isolated nucleic acid, naturally occurring or artifi EX25(a)855G), or the complement thereof. In specific cial, having a nucleotide sequence encoding a TLK1 protein embodiments, the isolated nucleic acid are oligonucleotides having an amino acid sequence according to SEQID NO:2 having a contiguous span of from about 17, 18, 19, 20, 21. but containing one or more amino acid variants of Tables 1-3 22, 23 or 25 to about 30, 40 or 50, preferably from about 21 (e.g., EX11(a).51G>A). Isolated nucleic acids having a nucle to about 30 nucleotide residues, of any TLK1 nucleic acid, otide sequence that is the complement of the sequence are said contiguous span containing one or more nucleotide also encompassed by the present invention. variants of Tables 1-3 (e.g., EX7(a)--63 A, EX7(a)+190C, EX 11(a)51A and EX25(a)855G). 0202) In addition, isolated nucleic acids are also provided which have a nucleotide sequence encoding a protein having 0209. In one embodiment, the isolated nucleic acid com an amino acid sequence that is at least 95%, preferably at prises a contiguous span of at least 12, 15, 17, 18, 19, 20, 21. least 97% and more preferably at least 99% identical to SEQ 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 50, 70 or 100 ID NO:2 but containing one or more amino acid variants of nucleotide residues of any one of SEQ ID NOS:3-10, con Tables 1-3 (e.g., EX11(a).51G>A), or the complement taining one or more nucleotide variants of Tables 1-3 (e.g., thereof. EX7(a)--63A, EX7(a)--190C, EX 11(a)51A and EX25(a)855G), or the complement thereof. In specific 0203 Also encompassed are isolated TLK1 nucleic acids embodiments, the isolated nucleic acid comprises a nucle obtainable by: otide sequence according to any one of SEQID NOS:3-10. (a) providing a human genomic library; In preferred embodiments, the isolated nucleic acid are oligonucleotides having a contiguous span of from about 17, (b) screening the genomic library using a probe having a 18, 19, 20, 21, 22, 23 or 25 to about 30, 40 or 50, preferably nucleotide sequence according to any one of SEQ ID NOs: from about 21 to about 30 nucleotide residues, of any one of 1, 3-10; and SEQ ID NOs: 3-10 and containing one or more nucleotide 0204 (c) producing a genomic DNA comprising a con variants of Tables 1-3 (e.g., EX7(a)--63 A, EX7(a)+190C, tiguous span of at least 30 nucleotides of any one of SEQID EX11(a)51A and EX25(a)855G). The complements of the NOs: 1, 3-10, wherein the genomic DNA thus produced isolated nucleic acids are also encompassed by the present contains one or more of the SNPs of the present invention in invention. Tables 1-3, such as EX7(a)--63 A, EX7(a)+190C, EX11(a).51A 0210 Thus, for example, an isolated nucleic acid of the and EX25(a)855G. present invention can have a contiguous span of at least 18, 0205 The present invention also includes isolated TLK1 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 or 40 or 50 nucleic acids obtainable by: nucleotide residues of SEQ ID NO:3 containing the nucle otide variant EX7(a)--63A (nucleotide residue No. 51 in SEQ (i) providing a cDNA library using human mRNA from a ID NO:3), or a contiguous span of at least 18, 19, 20, 21, 22. human tissue, e.g., blood; 23, 24, 25, 26, 27, 28, 29, or 30 or 40 or 50 nucleotide (ii) screening the cDNA library using a probe having a residues of SEQID NO:4 containing the nucleotide variant EX7(a)--190C (nucleotide residue No. 51 in SEQID NO:4), nucleotide sequence according to any one of SEQ ID NOs: or a contiguous span of at least 18, 19, 20, 21, 22, 23, 24, 25, 1, 3-10; and 26, 27, 28, 29, or 30 or 40 or 50 nucleotide residues of SEQ 0206 (iii) producing a cDNA DNA comprising a con ID NO:5 containing the nucleotide variant EX11(a)51A tiguous span of at least 30 nucleotides of any one of SEQID (nucleotide residue No. 51 in SEQID NO:5), or a contigu US 2007/0O82347 A1 Apr. 12, 2007 22 ous span of at least 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28. invention in Table 4, such as EX1(a)-963G, EX1(a)-103T. 29, or 30 or 40 or 50 nucleotide residues of SEQ ID NO:6 EX6(a)780G, EX6(a)842T and EX6(a)2152G. containing the nucleotide variant EX25(a)855G (nucleotide residue Nos. 51 in SEQ ID NO:6), or the complements 0218. The present invention also includes isolated thereof. WARS2 nucleic acids obtainable by: 0211 The present invention further provides an isolated (i) providing a cDNA library using human mRNA from a WARS2 nucleic acid containing at least one of the newly human tissue, e.g., blood; discovered nucleotide variants as Summarized in Table 4. (ii) screening the cDNA library using a probe having a e.g., EX1(a)-963G, EX1(a)-103T, EX6(a)780G, EX6(a)842T nucleotide sequence according to any one of SEQ ID NOs: and EX6(a)2152G. The term “WARS2 nucleic acid” is as defined above and means a naturally existing nucleic acid 18, 20, 22-26; and coding for a wild-type or variant or mutant WARS2. The 0219 (iii) producing a cDNA DNA comprising a con term “WARS2 nucleic acid' is inclusive and may be in the tiguous span of at least 30 nucleotides of any one of SEQID form of either double-stranded or single-stranded nucleic NOs: 18, 20, 22-26, wherein the cDNA thus produced acids, and a single strand can be either of the two comple contains one or more of the SNPs of the present invention in menting strands. The isolated WARS2 nucleic acid can be Table 4, such as EX1(a)-963G, EX1(a)-103T, EX6(a)780G, naturally existing genomic DNA, mRNA or cDNA. In one EX6(a)842T and EX6(a)2152G. embodiment, the isolated WARS2 nucleic acid has a nucle otide sequence encoding WARS2 protein having an amino 0220. The present invention also encompasses an isolated acid sequence according to SEQID NO:19 but contains one nucleic acid comprising the nucleotide sequence of a region or more amino acid variants. Isolated WARS2 nucleic acids of a WARS2 genomic DNA or cDNA or mRNA, wherein the having a nucleotide sequence that is the complement of the region contains one or more nucleotide variants as provided sequence are also encompassed by the present invention. in 4 (e.g., EX1(a)-963G, EX1(a)-103T, EX6(a)780G, EX6(a)842T and EX6(a)2 152G), or one or more nucleotide 0212. In yet another embodiment, the isolated WARS2 variants that will give rise to one or more amino acid nucleic acid has a nucleotide sequence encoding a WARS2 variants, or the complement thereof. Such regions can be protein having an amino acid sequence that is at least 95%, isolated and analyzed to efficiently detect the nucleotide preferably at least 97% and more preferably at least 99% variants of the present invention. Also, such regions can also identical to SEQID NO:19 but contains one or more amino be isolated and used as probes or primers in detection of the acid variants, or the complement thereof. nucleotide variants of the present invention and other uses as 0213 The present invention also provides an isolated will be clear from the descriptions below. nucleic acid, naturally occurring or artificial, having a nucle 0221) Thus, in one embodiment, the isolated nucleic acid otide sequence that is at least 95%, preferably at least 97% comprises a contiguous span of at least 12, 15, 17, 18, 19. and more preferably at least 99% identical to SEQID NO:18 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 50, 70 or 100 except for containing one or more nucleotide variants of nucleotide residues of a WARS2 nucleic acid, the contiguous Table 4 (e.g., EX1(a)-963G, EX1(a)-103T, EX6(a)780G, span containing one or more nucleotide variants of Table 4 EX6(a)842T and EX6(a)2152G), or the complement thereof. (e.g., EX1(a)-963G, EX1(a)-103T, EX6(a)780G, 0214. In another embodiment, the present invention pro EX6(a)842T and EX6(a)2152G), or the complement thereof. vides an isolated nucleic acid, naturally occurring or artifi In specific embodiments, the isolated nucleic acid are oli cial, having a nucleotide sequence encoding a WARS2 gonucleotides having a contiguous span of from about 17, protein having an amino acid sequence according to SEQID 18, 19, 20, 21, 22, 23 or 25 to about 30, 40 or 50, preferably NO:19 but containing one or more amino acid variants. from about 21 to about 30 nucleotide residues, of any Isolated nucleic acids having a nucleotide sequence that is WARS2 nucleic acid, said contiguous span containing one the complement of the sequence are also encompassed by or more nucleotide variants of Table 4 (e.g., EX1(a)-963G, the present invention. EX1(a)-103T, EX6(a)780G, EX6(a842T and EX6(a)2152G). 0215. In addition, isolated nucleic acids are also provided 0222. In one embodiment, the isolated nucleic acid com which have a nucleotide sequence encoding a protein having prises a contiguous span of at least 12, 15, 17, 18, 19, 20, 21. an amino acid sequence that is at least 95%, preferably at 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 50, 70 or 100 least 97% and more preferably at least 99% identical to SEQ nucleotide residues of any one of SEQ ID NOS:22-29, ID NO:19 but containing one or more amino acid variants, containing one or more nucleotide variants of Table 4 (e.g., or the complement thereof. EX1(a)-963G, EX1(a)-103T, EX6(a)780G, EX6(a)842T and EX6(a)2 152G), or the complement thereof. In specific 0216. Also encompassed are isolated WARS2 nucleic embodiments, the isolated nucleic acid comprises a nucle acids obtainable by: otide sequence according to any one of SEQID NOS: 22-29. (a) providing a human genomic library; In preferred embodiments, the isolated nucleic acid are (b) screening the genomic library using a probe having a oligonucleotides having a contiguous span of from about 17, nucleotide sequence according to any one of SEQ ID 18, 19, 20, 21, 22, 23 or 25 to about 30, 40 or 50, preferably from about 21 to about 30 nucleotide residues, of any one of NOS:18, 20, 22-26; and SEQID NOs: 22-29 and containing one or more nucleotide 0217 (c) producing a genomic DNA comprising a con variants of Table 4 (e.g., EX1(a)-963G, EX1(a)-103T, tiguous span of at least 30 nucleotides of any one of SEQID EX6(a)780G, EX6(a842T and EX6(a)2152G). The comple NOs: 18, 20, 22-26, wherein the genomic DNA thus pro ments of the isolated nucleic acids are also encompassed by duced contains one or more of the SNPs of the present the present invention. US 2007/0O82347 A1 Apr. 12, 2007

0223 Thus, for example, an isolated nucleic acid of the acid variants of Tables 5-11 (e.g., EX2(a)397C and present invention can have a contiguous span of at least 18, EX15(a)74A), or the complement thereof. 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 or 40 or 50 nucleotide residues of SEQID NO:22 containing the nucle 0228. The present invention also provides an isolated otide variant EX1(a)-963G (nucleotide residue No. 51 in nucleic acid, naturally occurring or artificial, having a nucle SEQID NO:22), or a contiguous span of at least 18, 19, 20, otide sequence that is at least 95%, preferably at least 97% 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 or 40 or 50 nucleotide and more preferably at least 99% identical to SEQID NO:30 residues of SEQID NO:23 containing the nucleotide variant except for containing one or more nucleotide variants of EX1(a)-103T (nucleotide residue No. 51 in SEQ ID NO: Tables 5-11 (e.g., EX2(a)397C and EX15(a)74A), or the 23), or a contiguous span of at least 18, 19, 20, 21, 22, 23, complement thereof. 24, 25, 26, 27, 28, 29, or 30 or 40 or 50 nucleotide residues 0229. In another embodiment, the present invention pro of SEQ ID NO:24 containing the nucleotide variant vides an isolated nucleic acid, naturally occurring or artifi EX6(a)780G (nucleotide residue No. 51 in SEQID NO:24), cial, having a nucleotide sequence encoding a ARTS1 pro or a contiguous span of at least 18, 19, 20, 21, 22, 23, 24, 25, tein having an amino acid sequence according to SEQ ID 26, 27, 28, 29, or 30 or 40 or 50 nucleotide residues of SEQ NO:31 but containing one or more amino acid variants of ID NO:25 containing the nucleotide variant EX6(a)842T Tables 5-11 (e.g., EX2(a)397C and EX15(a)74A). Isolated (nucleotide residue Nos. 51 in SEQ ID NO:25), or a con nucleic acids having a nucleotide sequence that is the tiguous span of at least 18, 19, 20, 21, 22, 23, 24, 25, 26, 27. complement of the sequence are also encompassed by the 28, 29, or 30 or 40 or 50 nucleotide residues of SEQ ID present invention. NO:26 containing the nucleotide variant EX6(a)2 152G (nucleotide residue Nos. 51 in SEQ ID NO:26), or the 0230. In addition, isolated nucleic acids are also provided complements thereof. which have a nucleotide sequence encoding a protein having an amino acid sequence that is at least 95%, preferably at 0224. The present invention further provides an isolated least 97% and more preferably at least 99% identical to SEQ ARTS1 nucleic acid containing at least one of the newly ID NO:31 but containing one or more amino acid variants of discovered nucleotide variants as Summarized in Tables Tables 5-11 (e.g., EX2(a)397C and EX15(a)74A), or the 5-10, or one or more nucleotide variants that will result in complement thereof. the amino acid variants provided in Tables 5-11, e.g., EX1(a)-1125T, EX2(a)397C, EX20(a) 1085G, EX15(a)74A, 0231. Also encompassed are isolated ARTS1 nucleic EX19(a)885T, EX20(a).2105C, EX20(a)719C and acids obtainable by: EX20(a) 1038A. The term “ARTS1 nucleic acid” is as (a) providing a human genomic library; defined above and means a naturally existing nucleic acid coding for a wild-type or variant or mutant ARTS1. The term (b) screening the genomic library using a probe having a “ARTS 1 nucleic acid is inclusive and may be in the form nucleotide sequence according to any one of SEQ ID of either double-stranded or single-stranded nucleic acids, NOs:30, 32, 34-35; and a single strand can be either of the two complementing 0232 (c) producing a genomic DNA comprising a con strands. The isolated ARTS1 nucleic acid can be naturally tiguous span of at least 30 nucleotides of any one of SEQID existing genomic DNA, mRNA or cDNA. In one embodi NOs: 30, 32, 34-35, wherein the genomic DNA thus pro ment, the isolated ARTS1 nucleic acid has a nucleotide duced contains one or more of the SNPs of the present sequence according to SEQID NO:30 but containing one or invention in Tables 5-11, such as EX1(a)-1125T. more exonic nucleotide variants of Tables 5-11 (e.g., EX2(a)397C, EX20(a) 1085G, EX15(a)74A, EX19(a)885T, EX2(a)397C and EX15(a)74A), or the complement thereof. EX20(a).2105C, EX20(a)719C and EX20(a) 1038A. 0225. In another embodiment, the isolated ARTS1 0233. The present invention also includes isolated nucleic acid has a nucleotide sequence that is at least 95%, ARTS1 nucleic acids obtainable by: preferably at least 97% and more preferably at least 99% identical to SEQID NO:30 but contains one or more exonic (i) providing a cDNA library using human mRNA from a nucleotide variants of Tables 5-11 (e.g., EX2(a)397C and human tissue, e.g., blood; EX15(a)74A), or one or more nucleotide variants that will (ii) screening the cDNA library using a probe having a result in one or more amino acid variants of Tables 5-11, or nucleotide sequence according to any one of SEQ ID Nos: the complement thereof. 30, 32, 34-35; and 0226. In yet another embodiment, the isolated ARTS1 0234 (iii) producing a cDNA DNA comprising a con nucleic acid has a nucleotide sequence encoding ARTS1 tiguous span of at least 30 nucleotides of any one of SEQID protein having an amino acid sequence according to SEQID NOs: 30, 32, 34-35, wherein the cDNA thus produced NO:31 but contains one or more amino acid variants of contains one or more of the SNPs of the present invention in Tables 5-11 (e.g., EX2(a)397C and EX15(a)74A). Isolated Tables 5-11, such as EX2(a)397C and EX15(a)74A. ARTS1 nucleic acids having a nucleotide sequence that is the complement of the sequence are also encompassed by 0235. The present invention also encompasses an isolated the present invention. nucleic acid comprising the nucleotide sequence of a region of a ARTS1 genomic DNA or cDNA or mRNA, wherein the 0227. In yet another embodiment, the isolated ARTS1 region contains one or more nucleotide variants as provided nucleic acid has a nucleotide sequence encoding a ARTS1 in Tables 5-11 (e.g., EX1(a)-1125T, EX2(a)397C, protein having an amino acid sequence that is at least 95%, EX20(a) 1085G, EX15(a)74A, EX19(a)885T, EX20(a).2105C, preferably at least 97% and more preferably at least 99% EX20(a)719C and EX20(a) 1038A), or one or more nucle identical to SEQID NO:31 but contains one or more amino otide variants that will give rise to one or more amino acid US 2007/0O82347 A1 Apr. 12, 2007 24 variants of Tables 5-11, or the complement thereof. Such or a contiguous span of at least 18, 19, 20, 21, 22, 23, 24, 25, regions can be isolated and analyzed to efficiently detect the 26, 27, 28, 29, or 30 or 40 or 50 nucleotide residues of SEQ nucleotide variants of the present invention. Also, Such ID NO:53 containing the nucleotide variant EX20(a).2105C regions can also be isolated and used as probes or primers in (nucleotide residue No. 51 in SEQ ID NO:53), or a con detection of the nucleotide variants of the present invention tiguous span of at least 18, 19, 20, 21, 22, 23, 24, 25, 26, 27. and other uses as will be clear from the descriptions below. 28, 29, or 30 or 40 or 50 nucleotide residues of SEQ ID NO:50 containing the nucleotide variant EX20(a)719C 0236. Thus, in one embodiment, the isolated nucleic acid (nucleotide residue No. 51 in SEQ ID NO:50), or a con comprises a contiguous span of at least 12, 15, 17, 18, 19. tiguous span of at least 18, 19, 20, 21, 22, 23, 24, 25, 26, 27. 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 50, 70 or 100 28, 29, or 30 or 40 or 50 nucleotide residues of SEQ ID nucleotide residues of a ARTS1 nucleic acid, the contiguous NO:51 containing the nucleotide variant EX20(a) 1038A span containing one or more nucleotide variants of Tables (nucleotide residue No. 51 in SEQ ID NO:51), or the 5-11 (e.g., EX1(a)-1125T, EX2(a)397C, EX20(a)1085G, complements thereof. EX15(a)74A, EX19(a)885T, EX20(a).2105C, EX20(a)719C and EX20(a) 1038A), or the complement thereof. In specific 0239). The present invention further provides an isolated embodiments, the isolated nucleic acid are oligonucleotides MSR nucleic acid containing at least one of the newly having a contiguous span of from about 17, 18, 19, 20, 21. discovered nucleotide variants as summarized in Table 12, 22, 23 or 25 to about 30, 40 or 50, preferably from about 21 or one or more nucleotide variants that will result in the to about 30 nucleotide residues, of any ARTS1 nucleic acid, amino acid variants provided in Table 12, e.g., EX1(a)- said contiguous span containing one or more nucleotide 674G, EX1(a) 19C, EX1(a)+129m, EX5(a)123T, EX10(a)+ variants of Tables 5-11 (e.g., EX1(a)-1125T, EX2(a)397C, 83G, EX11(a)+54C and EX14(a)14T. The term “MSR EX20(a) 1085G, EX15(a)74A, EX19(a)885T, EX20(a)2105C, nucleic acid is as defined above and means a naturally EX20(a)719C and EX20(a) 1038A). existing nucleic acid coding for a wild-type or variant or mutant MSR. The term "MSR nucleic acid' is inclusive and 0237. In one embodiment, the isolated nucleic acid com may be in the form of either double-stranded or single prises a contiguous span of at least 12, 15, 17, 18, 19, 20, 21. Stranded nucleic acids, and a single strand can be either of 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 50, 70 or 100 the two complementing strands. The isolated MSR nucleic nucleotide residues of any one of SEQ ID NOS: 26, 28. acid can be naturally existing genomic DNA, mRNA or 30-51, containing one or more nucleotide variants of Tables cDNA. In one embodiment, the isolated MSR nucleic acid 5-11 (e.g., EX1(a)-1125T, EX2(a)397C, EX20(a)1085G, has a nucleotide sequence according to SEQID NO:66 but EX15(a)74A, EX19(a)885T, EX20(a).2105C, EX20(a)719C containing one or more exonic nucleotide variants of Table and EX20(a) 1038A), or the complement thereof. In specific 12 (e.g., EX5(a)123T and EX14(a)14T), or the complement embodiments, the isolated nucleic acid comprises a nucle thereof. otide sequence according to any one of SEQID NOs: 30, 32, 34-35. In preferred embodiments, the isolated nucleic acid 0240. In another embodiment, the isolated MSR nucleic are oligonucleotides having a contiguous span of from about acid has a nucleotide sequence that is at least 95%, prefer 17, 18, 19, 20, 21, 22, 23 or 25 to about 30, 40 or 50, ably at least 97% and more preferably at least 99% identical preferably from about 21 to about 30 nucleotide residues, of to SEQ ID NO:64 but contains one or more exonic nucle any one of SEQID NOs: 30, 32, 34-35 and containing one otide variants of Table 12 (e.g., EX5(a)123T and or more nucleotide variants of Tables 5-11 (e.g., EX1(a)- EX14(a) 14T), or one or more nucleotide variants that will 1125T, EX2(a)397C, EX20(a) 1085G, EX15(a)74A, result in one or more amino acid variants of Table 12, or the EX 190885T, EX20(a).2105C, EX20(a)719C and complement thereof. EX20(a) 1038A). The complements of the isolated nucleic 0241. In yet another embodiment, the isolated MSR acids are also encompassed by the present invention. nucleic acid has a nucleotide sequence encoding MSR protein having an amino acid sequence according to SEQID 0238. Thus, for example, an isolated nucleic acid of the NO:67 but contains one or more amino acid variants of present invention can have a contiguous span of at least 18, Table 12 (e.g., EX14(a) 1.4T). Isolated MSR nucleic acids 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 or 40 or 50 having a nucleotide sequence that is the complement of the nucleotide residues of SEQ IUD NO:34 containing the sequence are also encompassed by the present invention. nucleotide variant EX1(a)-1125T (nucleotide residue No. 51 in SEQ ID NO:34), or a contiguous span of at least 18, 19. 0242. In yet another embodiment, the isolated MSR 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 or 40 or 50 nucleic acid has a nucleotide sequence encoding a MSR nucleotide residues of SEQID NO:35 containing the nucle protein having an amino acid sequence that is at least 95%, otide variant EX2(a)397C (nucleotide residue No. 51 in SEQ preferably at least 97% and more preferably at least 99% ID NO:35), or a contiguous span of at least 18, 19, 20, 21, identical to SEQID NO:65 but contains one or more amino 22, 23, 24, 25, 26, 27, 28, 29, or 30 or 40 or 50 nucleotide acid variants of Table 12 (e.g., EX14(a)14T), or the comple residues of SEQ ID NO:52 containing the nucleotide vari ment thereof. ant, EX20(a) 1085G (nucleotide residue No. 51 in SEQ ID 0243 The present invention also provides an isolated NO:52), or a contiguous span of at least 18, 19, 20, 21, 22. nucleic acid, naturally occurring or artificial, having a nucle 23, 24, 25, 26, 27, 28, 29, or 30 or 40 or 50 nucleotide otide sequence that is at least 95%, preferably at least 97% residues of SEQID NO:45 containing the nucleotide variant and more preferably at least 99% identical to SEQID NO:66 EX15(a)74A (nucleotide residue Nos. 51, 52 and 53 in SEQ except for containing one or more nucleotide variants of ID NO:45), or a contiguous span of at least 18, 19, 20, 21, Table 12 (e.g., EX5(a) 123T and EX14(a) 14T), or the comple 22, 23, 24, 25, 26, 27, 28, 29, or 30 or 40 or 50 nucleotide ment thereof. residues of SEQID NO:49 containing the nucleotide variant 0244. In another embodiment, the present invention pro EX19(a)885T (nucleotide residue No. 51 in SEQID NO:49), vides an isolated nucleic acid, naturally occurring or artifi US 2007/0O82347 A1 Apr. 12, 2007 cial, having a nucleotide sequence encoding a MSR protein isolated nucleic acid are oligonucleotides having a contigu having an amino acid sequence according to SEQID NO:67 ous span of from about 17, 18, 19, 20, 21, 22, 23 or 25 to but containing one or more amino acid variants of Table 12 about 30, 40 or 50, preferably from about 21 to about 30 (e.g., EX14(a) 1.4T). Isolated nucleic acids having a nucle nucleotide residues, of any MSR nucleic acid, said contigu otide sequence that is the complement of the sequence are ous span containing one or more nucleotide variants of Table also encompassed by the present invention. 12 (e.g., EX1(a)-674G, EX1(a) 19C, EX1(a)+129m, 0245. In addition, isolated nucleic acids are also provided EX5(a)123T, EX10(a)+83G, EX11(a)+54C and EX14(a)14T). which have a nucleotide sequence encoding a protein having 0252) In one embodiment, the isolated nucleic acid com an amino acid sequence that is at least 95%, preferably at prises a contiguous span of at least 12, 15, 17, 18, 19, 20, 21. least 97% and more preferably at least 99% identical to SEQ 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 50, 70 or 100 ID NO:67 but containing one or more amino acid variants of nucleotide residues of any one of SEQ ID NOS:70-81, Table 12 (e.g., EX14(a)14T), or the complement thereof. containing one or more nucleotide variants of Table 12 (e.g., EX1(a)-674G, EX1(a) 19C, EX1(a)+129m, EX5(a)123T, 0246 Also encompassed are isolated MSR nucleic acids EX10(a)+83G, EX11(a)+54C and EX14(a)14T), or the obtainable by: complement thereof. In specific embodiments, the isolated (a) providing a human genomic library; nucleic acid comprises a nucleotide sequence according to any one of SEQ ID NOS:70-81. In preferred embodiments, (b) screening the genomic library using a probe having a the isolated nucleic acid are oligonucleotides having a nucleotide sequence according to any one of SEQ ID contiguous span of from about 17, 18, 19, 20, 21, 22, 23 or NOs:66, 68, 70-81; and 25 to about 30, 40 or 50, preferably from about 21 to about 0247 (c) producing a genomic DNA comprising a con 30 nucleotide residues, of any one of SEQ ID NOS:70-81 tiguous span of at least 30 nucleotides of any one of SEQID and containing one or more nucleotide variants of Table 12 NOs: 66, 68, 70-81, wherein the genomic DNA thus pro (e.g., EX1(a)-674G, EX1(a) 19C, EX1(a)+129m, duced contains one or more of the SNPs of the present EX5(a)123T, EX10(a)+83G, EX11(a)+54C and EX14(a)14T). invention in Table 12, such as EX1(a)-674G, EX1(a) 19C, The complements of the isolated nucleic acids are also EX1(a)+129m, EX5(a)123T, EX10(a)+83G, EX11(a)+54C encompassed by the present invention. and EX14(a)14T. 0253 For example, an isolated nucleic acid of the present 0248. The present invention also includes isolated MSR invention can have a contiguous span of at least 18, 19, 20, nucleic acids obtainable by: 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 or 40 or 50 nucleotide residues of SEQID NO:70 containing the nucleotide variant (i) providing a cDNA library using human mRNA from a EX1(a)-674G (nucleotide residue No. 51 in SEQ ID human tissue, e.g., blood; NO:70), or a contiguous span of at least 18, 19, 20, 21, 22. (ii) screening the cDNA library using a probe having a 23, 24, 25, 26, 27, 28, 29, or 30 or 40 or 50 nucleotide nucleotide sequence according to any one of SEQ ID NOs: residues of SEQID NO:71 containing the nucleotide variant 66, 68, 70-81; and EX1(a) 19C (nucleotide residue No. 51 in SEQID NO:71), or 0249 (iii) producing a cDNA DNA comprising a con a contiguous span of at least 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 or 40 or 50 nucleotide residues of SEQ tiguous span of at least 30 nucleotides of any one of SEQID ID NO:72 containing the nucleotide variant EX1(a)+129m NOs: 66, 68, 70-81, wherein the cDNA thus produced (nucleotide residue No. 51 in SEQ ID NO:72), or a con contains one or more of the SNPs of the present invention in tiguous span of at least 18, 19, 20, 21, 22, 23, 24, 25, 26, 27. Table 12, such as EX5(a)123T and EX14(a)14T. 28, 29, or 30 or 40 or 50 nucleotide residues of SEQ ID 0250) The present invention also encompasses an isolated NO:73 containing the nucleotide variant EX5(a)123T (nucle nucleic acid comprising the nucleotide sequence of a region otide residue Nos. 51 in SEQ ID NO:73), or a contiguous of a MSR genomic DNA or cDNA or mRNA, wherein the span of at least 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29. region contains one or more nucleotide variants as provided or 30 or 40 or 50 nucleotide residues of SEQ ID NO:76 in Table 12 (e.g., EX1(a)-674G, EX1(a) 19C, EX1(a)+129m, containing the nucleotide variant EX10(a)+83G (nucleotide EX5(a)123T, EX10(a)+83G, EX11(a)+54C and EX14(a)14T), residue Nos. 51 in SEQID NO:76), or a contiguous span of or one or more nucleotide variants that will give rise to one at least 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 or more amino acid variants of Table 12, or the complement or 40 or 50 nucleotide residues of SEQID NO:77 containing thereof. Such regions can be isolated and analyzed to the nucleotide variant EX11(a)+54C (nucleotide residue efficiently detect the nucleotide variants of the present Nos. 51 in SEQID NO:77), or a contiguous span of at least invention. Also, Such regions can also be isolated and used 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 or 40 or as probes or primers in detection of the nucleotide variants 50 nucleotide residues of SEQ ID NO:78 containing the of the present invention and other uses as will be clear from nucleotide variant EX14(a)14T (nucleotide residue Nos. 51 the descriptions below. in SEQ ID NO:78), or the complements thereof. 0251 Thus, in one embodiment, the isolated nucleic acid 0254 The present invention further provides an isolated comprises a contiguous span of at least 12, 15, 17, 18, 19. AKAP9 nucleic acid containing at least one of the newly 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 50, 70 or 100 discovered nucleotide variants as summarized in Table 13, nucleotide residues of a MSR nucleic acid, the contiguous or one or more nucleotide variants that will result in the span containing one or more nucleotide variants of Table 12 amino acid variants provided in Table 13, e.g., (e.g., EX1(a)-674G, EX1(a) 19C, EX1(a)+129m, EX 10(a)186G, EX16(a)-59G, EX39(a)121T, EX40(a)470A, EX5(a)123T, EX10(a)+83G, EX11(a)+54C and EX14(a)14T), EX40(a) 1055G and EX19(a)1101C. The term “AKAP9 or the complement thereof. In specific embodiments, the nucleic acid is as defined above and means a naturally US 2007/0O82347 A1 Apr. 12, 2007 26 existing nucleic acid coding for a wild-type or variant or 0262 (c) producing a genomic DNA comprising a con mutant AKAP9. The term “AKAP9 nucleic acid is inclu tiguous span of at least 30 nucleotides of any one of SEQID sive and may be in the form of either double-stranded or NOs: 90, 92-94, 96-120, wherein the genomic DNA thus single-stranded nucleic acids, and a single strand can be produced contains one or more of the SNPs of the present either of the two complementing strands. The isolated invention in Tables 13 and/or 14, such as EX10(a) 186G, AKAP9 nucleic acid can be naturally existing genomic EX16(a)-59G, EX39(a)121T, EX40(a)470A, EX40(a)1055G DNA, mRNA or cDNA. In one embodiment, the isolated and EX19(a) 1011C. AKAP9 nucleic acid has a nucleotide sequence according to 0263. The present invention also includes AKAP9 SEQ ID NO:90 but containing one or more exonic nucle nucleic acids obtainable by: otide variants of Table 13 (e.g., EX10(a) 186G and EX39(a)121T), or the complement thereof. (i) providing a cDNA library using human mRNA from a human tissue, e.g., blood; 0255. In another embodiment, the isolated AKAP9 nucleic acid has a nucleotide sequence that is at least 95%, (ii) screening the cDNA library using a probe having a preferably at least 97% and more preferably at least 99% nucleotide sequence according to any one of SEQ ID identical to SEQID NO:90 but contains one or more exonic NOs:90, 96-120; and nucleotide variants of Tables 13 and 14 (e.g., EX10(a)186G and EX39(a)121T), or one or more nucleotide variants that 0264 (iii) producing a cDNA DNA comprising a con will result in one or more amino acid variants of Tables 13 tiguous span of at least 30 nucleotides of any one of SEQID and/or 14, or the complement thereof. NOs: 90,96-120, wherein the cDNA thus produced contains one or more of the SNPs of the present invention in Tables 0256 In yet another embodiment, the isolated AKAP9 nucleic acid has a nucleotide sequence encoding AKAP9 13 and/or 14, such as EX10(a)186G and EX39(a)121T. protein having an amino acid sequence according to SEQID 0265. The present invention also encompasses an isolated NO:91 but contains one or more amino acid variants of nucleic acid comprising the nucleotide sequence of a region Table 13 and/or 14 (e.g., EX9(a)459T and EX35(a)215G). of a AKAP9 genomic DNA or cDNA or mRNA, wherein the Isolated AKAP9 nucleic acids having a nucleotide sequence region contains one or more nucleotide variants as provided that is the complement of the sequence are also encom in Tables 13 and 14 (e.g., EX10(a)186G, EX16(a)-59G, passed by the present invention. EX39(a)121T, EX40(a)470A, EX40(a) 1055G and 0257). In yet another embodiment, the isolated AKAP9 EX19(a) 1011C), or one or more nucleotide variants that will nucleic acid has a nucleotide sequence encoding a AKAP9 give rise to one or more amino acid variants of Tables 13 protein having an amino acid sequence that is at least 95%, and/or 14, or the complement thereof. Such regions can be preferably at least 97% and more preferably at least 99% isolated and analyzed to efficiently detect the nucleotide identical to SEQID NO:91 but contains one or more amino variants of the present invention. Also, such regions can also acid variants of Table 13 and/or 14 (e.g., EX9(a)459T and be isolated and used as probes or primers in detection of the EX35(a).215G), or the complement thereof. nucleotide variants of the present invention and other uses as 0258. The present invention also provides an isolated will be clear from the descriptions below. nucleic acid, naturally occurring or artificial, having a nucle otide sequence that is at least 95%, preferably at least 97% 0266 Thus, in one embodiment, the isolated nucleic acid and more preferably at least 99% identical to SEQID NO:90 comprises a contiguous span of at least 12, 15, 17, 18, 19. except for containing one or more nucleotide variants of 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 50, 70 or 100 Tables 13 and/or 14 (e.g., EX10(a) 186G and EX39(a)121T), nucleotide residues of a AKAP9 nucleic acid, the contiguous or the complement thereof. span containing one or more nucleotide variants of Tables 13 and/or 14 (e.g., EX10186G, EX16(a)-59G, EX39(a)121T, 0259. In another embodiment, the present invention pro EX40(a)470A, EX40(a)1055G and EX19(a) 1011C), or the vides an isolated nucleic acid, naturally occurring or artifi complement thereof. In specific embodiments, the isolated cial, having a nucleotide sequence encoding a AKAP9 nucleic acids are oligonucleotides having a contiguous span protein having an amino acid sequence according to SEQID NO:91 but containing one or more amino acid variants of of from about 17, 18, 19, 20, 21, 22, 23 or 25 to about 30, Table 13 and/or 14 (e.g., EX9(a)459T and EX35(a)215G). 40 or 50, preferably from about 21 to about 30 nucleotide Isolated nucleic acids having a nucleotide sequence that is residues, of any AKAP9 nucleic acid, said contiguous span the complement of the sequence are also encompassed by containing one or more nucleotide variants of Tables 13 the present invention. and/or 14 (e.g., EX10(a)186G, EX16(a)-59G, EX39(a)121T, EX40(a)470A, EX40(a)1055G and EX19(a) 1011C). 0260. In addition, isolated nucleic acids are also provided which have a nucleotide sequence encoding a protein having 0267 In one embodiment, the isolated nucleic acid com an amino acid sequence that is at least 95%, preferably at prises a contiguous span of at least 12, 15, 17, 18, 19, 20, 21. least 97% and more preferably at least 99% identical to SEQ 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 50, 70 or 100 ID NO:91 but containing one or more amino acid variants of nucleotide residues of any one of SEQ ID NOs: 96-120, Table 13 and/or 14 (e.g., EX9(a)459T and EX35(a).215G), or containing one or more nucleotide variants of Tables 13 and the complement thereof. 14 (e.g., EX10(a)186G, EX16(a)-59G, EX39(a)121T, 0261 Also encompassed are isolated AKAP9 nucleic EX40(a)470A, EX40(a)1055G and EX19(a) 1011C), or the acids obtainable by: complement thereof. In specific embodiments, the isolated nucleic acid comprises a nucleotide sequence according to (a) providing a human genomic library; any one of SEQID NOs: 96-120. In preferred embodiments, (b) screening the genomic library using a probe having a the isolated nucleic acids are oligonucleotides having a nucleotide sequence according to any one of SEQ ID contiguous span of from about 17, 18, 19, 20, 21, 22, 23 or NOs:90, 92-94, 96-120; and 25 to about 30, 40 or 50, preferably from about 21 to about US 2007/0O82347 A1 Apr. 12, 2007 27

30 nucleotide residues, of any one of SEQ ID NOs: 92-116 NO:150 but contains one or more amino acid variants of and containing one or more nucleotide variants of Tables 13 Tables 15 and/or 16 (e.g., EX1(a)527G). Isolated DNAJD1 and/or 14 (e.g., EX10(a) 186G, EX16(a)-59G, EX39(a)121T, nucleic acids having a nucleotide sequence that is the EX40(a)470A, EX40(a) 1055G and EX19(a) 1011C). The complement of the sequence are also encompassed by the complements of the isolated nucleic acids are also encom present invention. passed by the present invention. 0272. In yet another embodiment, the isolated DNAJD1 0268 Thus, for example, an isolated nucleic acid of the nucleic acid has a nucleotide sequence encoding a DNAJD1 present invention can have a contiguous span of at least 18, protein having an amino acid sequence that is at least 95%, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 or 40 or 50 preferably at least 97% and more preferably at least 99% nucleotide residues of SEQ ID NO:100 containing the identical to SEQID NO:150 but contains one or more amino nucleotide variant EX10(a)186G (nucleotide residue No. 51 acid variants of Tables 15 and/or 16 (e.g., EX1(a)527G), or in SEQID NO:100), or a contiguous span of at least 18, 19. the complement thereof. 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 or 40 or 50 0273. The present invention also provides an isolated nucleotide residues of SEQ ID NO:102 containing the nucleic acid, naturally occurring or artificial, having a nucle nucleotide variant EX1616-59G (nucleotide residue No. 51 otide sequence that is at least 95%, preferably at least 97% in SEQID NO:102), or a contiguous span of at least 18, 19. and more preferably at least 99% identical to SEQ ID 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 or 40 or 50 NO:149 except for containing one or more nucleotide vari nucleotide residues of SEQ ID NO:100 containing the ants of Tables 15 and/or 16 (e.g., EX1(a)527G), or the nucleotide variant EX39(a)121T (nucleotide residue No. 110 complement thereof. in SEQID NO: 106), or a contiguous span of at least 18, 19. 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 or 40 or 50 0274. In another embodiment, the present invention pro nucleotide residues of SEQID NO:111 containing the nucle vides an isolated nucleic acid, naturally occurring or artifi otide variant EX40(a)470A (nucleotide residue Nos. 51 in cial, having a nucleotide sequence encoding a DNAJD1 SEQ ID NO:1111), or a contiguous span of at least 18, 19. protein having an amino acid sequence according to SEQID 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 or 40 or 50 NO:150 but containing one or more amino acid variants of nucleotide residues of SEQ ID NO: 113 containing the Tables 15 and/or 16 (e.g., EX1(a)527G). Isolated nucleic nucleotide variant EX40(a) 1055G (nucleotide residue Nos. acids having a nucleotide sequence that is the complement 51, 52 and 53 in SEQID NO:113), or a contiguous span of of the sequence are also encompassed by the present inven at least 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 tion. or 40 or 50 nucleotide residues of SEQID NO:117 contain 0275. In addition, isolated nucleic acids are also provided ing the nucleotide variant EX19(a) 1011 (nucleotide residue which have a nucleotide sequence encoding a protein having Nos. 51, 52 and 53 in SEQID NO:117), or the complements an amino acid sequence that is at least 95%, preferably at thereof. least 97% and more preferably at least 99% identical to SEQ 0269. The present invention further provides an isolated ID NO:150 but containing the amino acid variant of Tables DNAJD1 nucleic acid containing at least one of the newly 15 and/or 16 (e.g., EX1(a)527G), or the complement thereof. discovered nucleotide variants as summarized in Tables 15 0276 Also encompassed are isolated DNAJD1 nucleic and 16, or one or more nucleotide variants that will result in acids obtainable by: the amino acid variants provided in Tables 15 and/or 16, e.g., EX1(a)527G. The term “DNAJD1 nucleic acid” is as defined (a) providing a human genomic library; above and means a naturally existing nucleic acid coding for (b) screening the genomic library using a probe having a a wild-type or variant or mutant DNAJD1. The term nucleotide sequence according to any one of SEQ ID “DNAJD1 nucleic acid is inclusive and may be in the form NOs: 149, 151-153; and of either double-stranded or single-stranded nucleic acids, and a single strand can be either of the two complementing 0277 (c) producing a genomic DNA comprising a con strands. The isolated DNAJD1 nucleic acid can be naturally tiguous span of at least 30 nucleotides of any one of SEQID existing genomic DNA, mRNA or cDNA. In one embodi NOs: 149, 151-153, wherein the genomic DNA thus pro ment, the isolated DNAJD1 nucleic acid has a nucleotide duced contains one or more of the SNPs of the present sequence according to SEQID NO:149 but containing one invention in Tables 15 and/or 16, such as EX1(a).527G, or more exonic nucleotide variants of Tables 15 and/or 16 EX1(a)368T and EX5(a)+72m. (e.g., EX1(a).527G, and EX1(a)368T), or the complement 0278. The present invention also includes isolated thereof. DNAJD1 nucleic acids obtainable by: 0270. In another embodiment, the isolated DNAJD1 (i) providing a cDNA library using human mRNA from a nucleic acid has a nucleotide sequence that is at least 95%, human tissue, e.g., blood; preferably at least 97% and more preferably at least 99% (ii) screening the cDNA library using a probe having a identical to SEQID NO: 149 but contains one or more exonic nucleotide sequence according to any one of SEQ ID NOs: nucleotide variants of Tables 15 and/or 16 (e.g., EX1(a)527G 149, 151-153; and and EX1(a)368T), or one or more nucleotide variants that will result in one or more amino acid variants of Tables 15 0279 (iii) producing a cDNA DNA comprising a con and/or 16, or the complement thereof. tiguous span of at least 30 nucleotides of any one of SEQID NOs: 149, 151-153, wherein the cDNA thus produced 0271 In yet another embodiment, the isolated DNAJD1 contains one or more of the SNPs of the present invention in nucleic acid has a nucleotide sequence encoding DNAJD1 Tables 15 and/or 16, such as EX1(a).527G, EX1(a)368T and protein having an amino acid sequence according to SEQID EX5(a)+72m. US 2007/0O82347 A1 Apr. 12, 2007 28

0280 The present invention also encompasses an isolated Table 17, or one or more nucleotide variants that will result nucleic acid comprising the nucleotide sequence of a region in the amino acid variants provided in Table 17, e.g., of a DNAJD1 genomic DNA or cDNA or mRNA, wherein EX 15(a)-85G, EX15(a)+86G, EX16(a)323A, EX16(a)737G. the region contains one or more nucleotide variants as The term “GOLPH4 nucleic acid' is as defined above and provided in Tables 15 and/or 16 (e.g., EX1(a).527G, means a naturally existing nucleic acid coding for a wild EX1(a)368T and EX5(a)+72m), or one or more nucleotide type or variant or mutant GOLPH4. The term “GOLPH4 variants that will give rise to one or more amino acid nucleic acid is inclusive and may be in the form of either variants of Tables 15 and/or 16, or the complement thereof. double-stranded or single-stranded nucleic acids, and a Such regions can be isolated and analyzed to efficiently single strand can be either of the two complementing detect the nucleotide variants of the present invention. Also, strands. The isolated GOLPH4 nucleic acid can be naturally Such regions can also be isolated and used as probes or existing genomic DNA, mRNA or cDNA. In one embodi primers in detection of the nucleotide variants of the present ment, the isolated GOLPH4 nucleic acid has a nucleotide invention and other uses as will be clear from the descrip sequence according to SEQID NO:153 but containing one tions below. or more exonic nucleotide variants of Tables 17 and/or 18 (e.g., EX15(a)-85G, EX15(a)+86G, EX16(a)323A, 0281. Thus, in one embodiment, the isolated nucleic acid comprises a contiguous span of at least 12, 15, 17, 18, 19. EX16(a)737G) or the complement thereof. 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 50, 70 or 100 0285) In yet another embodiment, the isolated GOLPH4 nucleotide residues of a DNAJD1 nucleic acid, the contigu nucleic acid has a nucleotide sequence encoding GOLPH4 ous span containing one or more nucleotide variants of protein having an amino acid sequence according to SEQID Tables 15 and/or 16 (e.g., EX1(a)527G, EX1(a)368T and NO:157 but contains one or more amino acid variants of EX5(a)+72m), or the complement thereof. In specific Tables 17 and/or 18. Isolated GOLPH4 nucleic acids having embodiments, the isolated nucleic acid are oligonucleotides a nucleotide sequence that is the complement of the having a contiguous span of from about 17, 18, 19, 20, 21. sequence are also encompassed by the present invention. 22, 23 or 25 to about 30, 40 or 50, preferably from about 21 0286 The present invention also provides an isolated to about 30 nucleotide residues, of any DNAJD1 nucleic nucleic acid, naturally occurring or artificial, having a nucle acid, said contiguous span containing one or more nucle otide sequence that is at least 95%, preferably at least 97% otide variants of Tables 15 and/or 16 (e.g., EX1(a).527G, and more preferably at least 99% identical to SEQ ID EX1(a)368T and EX5(a)+72m). NO:156 except for containing one or more nucleotide vari 0282. In one embodiment, the isolated nucleic acid com ants of Tables 17 and/or 18 (e.g. EX15(a)-85G, EX15(a)+ prises a contiguous span of at least 12, 15, 17, 18, 19, 20, 21. 86G, EX16(a)323A, EX16(a)737G), or the complement 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 50, 70 or 100 thereof. nucleotide residues of any one of SEQ ID NOs: 147-151, 0287 Also encompassed are isolated GOLPH4 nucleic containing one or more nucleotide variants of Tables 15 acids obtainable by: and/or 16 (e.g., EX1(a)527G, EX1(a)368T and EX5(a)+72m), or the complement thereof. In specific embodiments, the (a) providing a human genomic library; isolated nucleic acid comprises a nucleotide sequence (b) screening the genomic library using a probe having a according to any one of SEQID NOs: 151-153. In preferred nucleotide sequence according to anyone of SEQ ID embodiments, the isolated nucleic acid are oligonucleotides NOs: 152, 154-159; and having a contiguous span of from about 17, 18, 19, 20, 21. 22, 23 or 25 to about 30, 40 or 50, preferably from about 21 0288 (c) producing a genomic DNA comprising a con to about 30 nucleotide residues, of any one of SEQID NOs: tiguous span of at least 30 nucleotides of any one of SEQID 151-153 and containing one or more nucleotide variants of NOs: 152, 154-159, wherein the genomic DNA thus pro Tables 15 and/or 16 (e.g., EX1(a)527G, EX1(a)368T and duced contains one or more of the SNPs of the present EX5(a)+72m). The complements of the isolated nucleic invention in Tables 17 and/or 18, such as EX15(a)-85G, acids are also encompassed by the present invention. EX 15(a)+86G, EX16(a)323A, EX16(a)737G. 0283 Thus, for example, an isolated nucleic acid of the 0289. The present invention also includes isolated present invention can have a contiguous span of at least 18, GOLPH4 nucleic acids obtainable by: 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 or 40 or 50 (i) providing a cDNA library using human mRNA from a nucleotide residues of SEQ ID NO:151 containing the human tissue, e.g., blood; nucleotide variant EX1(a)368T (nucleotide residue No. 51 in SEQID NO:151), or a contiguous span of at least 18, 19, 20, (ii) screening the cDNA library using a probe having a 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 or 40 or 50 nucleotide nucleotide sequence according to any one of SEQ ID NOs: residues of SEQ ID NO:152 containing the nucleotide 152, 154-159; and variant EX1(a)527G (nucleotide residue No. 51 in SEQ ID 0290 (iii) producing a cDNA DNA comprising a con NO:152), or a contiguous span of at least 18, 19, 20, 21, 22. tiguous span of at least 30 nucleotides of any one of SEQID 23, 24, 25, 26, 27, 28, 29, or 30 or 40 or 50 nucleotide NOs: 152, 154-159, wherein the cDNA thus produced residues of SEQ ID NO: 153 containing the nucleotide contains one or more of the SNPs of the present invention in variant EX1(a)+72m (nucleotide residue No. 51-53 in SEQ Tables 17 and/or 18, such as EX15(a)-85G, EX15(a)+86G, ID NO:153), or the complements thereof. EX16(a)323A, EX16(a)737G. 0284. Accordingly, the present invention provides an 0291. The present invention also encompasses an isolated isolated GOLPH4 nucleic acid containing at least one of the nucleic acid comprising the nucleotide sequence of a region newly discovered nucleotide variants as Summarized in of a GOLPH4 genomic DNA or cDNA or mRNA, wherein US 2007/0O82347 A1 Apr. 12, 2007 29 the region contains one or more nucleotide variants as 0295) The present invention further provides an isolated provided in Tables 17 and/or 18 (e.g., EX15(a)-85G, RABEP1 nucleic acid containing at least one of the newly EX15(a)+86G, EX16(a)323A, EX16(a)737G), or one or more discovered nucleotide variants as Summarized in Tables nucleotide variants that will give rise to one or more amino 19-22, or one or more nucleotide variants that will result in acid variants of Tables 17 and/or 18, or the complement the amino acid variants provided in Tables 19-23, e.g., thereof. Such regions can be isolated and analyzed to EX1(a)-511T, EX18(a)646m, EX18(a)690m, EX18(a)903m, efficiently detect the nucleotide variants of the present EX18(a) 1689m and EX18(a)2373m. The term “RABEP1 nucleic acid is as defined above and means a naturally invention. Also, Such regions can also be isolated and used existing nucleic acid coding for a wild-type or variant or as probes or primers in detection of the nucleotide variants mutant RABEP1. The term “RABEP1 nucleic acid is of the present invention and other uses as will be clear from inclusive and may be in the form of either double-stranded the descriptions below. or single-stranded nucleic acids, and a single Strand can be 0292. Thus, in one embodiment, the isolated nucleic acid either of the two complementing strands. The isolated comprises a contiguous span of at least 12, 15, 17, 18, 19. RABEP1 nucleic acid can be naturally existing genomic 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 50, 70 or 100 DNA, mRNA or cDNA. In one embodiment, the isolated nucleotide residues of a GOLPH4 nucleic acid, the contigu RABEP1 nucleic acid has a nucleotide sequence according ous span containing one or more nucleotide variants of to SEQ ID NO: 170 but containing one or more exonic Tables 17 and/or 18 (e.g. EX15(a)-85G, EX15(a)+86G, nucleotide variants of Tables 19-23 (e.g., EX1(a)73C, EX16(a)323A, EX16(a)737G), or the complement thereof. In EX 14(a)30C, EX17(a) 15G, EX17(a)36C and EX17(a)87A), specific embodiments, the isolated nucleic acid are oligo or the complement thereof. nucleotides having a contiguous span of from about 17, 18, 0296) In another embodiment, the isolated RABEP1 19, 20, 21, 22, 23 or 25 to about 30, 40 or 50, preferably nucleic acid has a nucleotide sequence that is at least 95%, from about 21 to about 30 nucleotide residues, of any preferably at least 97% and more preferably at least 99% GOLPH4 nucleic acid, said contiguous span containing one identical to SEQID NO:162 but contains one or more exonic or more nucleotide variants of Tables 17 and/or 18 (e.g. nucleotide variants of Tables 19-23 (e.g., EX1(a)73C, EX 15(a)-85G, EX15(a)+86G, EX16(a)323A, EX16(a)737G). EX 14(a)30C, EX17(a) 15G, EX17(a)36C and EX17(a)87A), 0293. In one embodiment, the isolated nucleic acid com or one or more nucleotide variants that will result in one or prises a contiguous span of at least 12, 15, 17, 18, 19, 20, 21. more amino acid variants of Tables 19-23, or the comple 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 50, 70 or 100 ment thereof. nucleotide residues of any one of SEQ ID NOS:158-167, 0297. The present invention also provides an isolated containing one or more nucleotide variants of Tables 17 nucleic acid, naturally occurring or artificial, having a nucle and/or 18 (e.g., EX15(a)-85G, EX15(a)+86G, EX16(a)323A, otide sequence that is at least 95%, preferably at least 97% EX16(a)737G), or the complement thereof. In specific and more preferably at least 99% identical to SEQ ID embodiments, the isolated nucleic acid comprises a nucle NO: 170 except for containing one or more nucleotide vari otide sequence according to any one of SEQ ID NOs: ants of Tables 19-23 (e.g., EX1(a)73C, EX14(a)30C, 158-167. In preferred embodiments, the isolated nucleic acid EX17(a) 15G, EX17(a)36C and EX17(a)87A), or the comple are oligonucleotides having a contiguous span of from about ment thereof. 17, 18, 19, 20, 21, 22, 23 or 25 to about 30, 40 or 50, preferably from about 21 to about 30 nucleotide residues, of 0298 Also encompassed are isolated RABEP1 nucleic any one of SEQ ID NOs: 158-167 and containing one or acids obtainable by: more nucleotide variants of Tables 17 and/or 18 (e.g., (a) providing a human genomic library; EX 15(a)-85G, EX15(a)+86G, EX16(a)323A, EX16(a)737G). The complements of the isolated nucleic acids are also (b) screening the genomic library using a probe having a encompassed by the present invention. nucleotide sequence according to any one of SEQ ID NOs: 170, 172-196; and 0294 Thus, for example, an isolated nucleic acid of the present invention can have a contiguous span of at least 18, 0299 (c) producing a genomic DNA comprising a con 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 or 40 or 50 tiguous span of at least 30 nucleotides of any one of SEQID nucleotide residues of SEQ ID NO:159 containing the NOs: 170, 172-196, wherein the genomic DNA thus pro nucleotide variant EX15(a)-85G (nucleotide residue No. 51 duced contains one or more of the SNPs of the present in SEQID NO:159), or a contiguous span of at least 18, 19. invention in Tables 19-23, such as EX1(a)-551T, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 or 40 or 50 EX18(a)646m, EX18(a)690m, EX18(a)903m, EX18(a) 1689m nucleotide residues of SEQ ID NO:160 containing the and EX18(a)2373m. nucleotide variant EX15(a)+86G (nucleotide residue No. 51 0300. The present invention also includes isolated in SEQID NO:160), or a contiguous span of at least 18, 19. RABEP1 nucleic acids obtainable by: 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 or 40 or 50 nucleotide residues of SEQ ID NO:161 containing the (i) providing a cDNA library using human mRNA from a nucleotide variant EX16(a)323A (nucleotide residue No. 51 human tissue, e.g., blood; in SEQID NO:161), or a contiguous span of at least 18, 19. (ii) screening the cDNA library using a probe having a 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 or 40 or 50 nucleotide sequence according to any one of SEQ ID nucleotide residues of SEQ ID NO:162 containing the NOs: 170, 172-196; and nucleotide variant EX16(a)737G (nucleotide residue Nos. 51, 52 and 53 in SEQ ID NO:162), or the complements 0301 (iii) producing a cDNA DNA comprising a con thereof. tiguous span of at least 30 nucleotides of any one of SEQID US 2007/0O82347 A1 Apr. 12, 2007 30

NOs: 170, 172-196, wherein the cDNA thus produced con 51-69 in SEQID NO:180), or a contiguous span of at least tains one or more of the SNPs of the present invention in 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 or 40 or Tables 19-23, such as EX1(a) 173C, EX14(a)30C, 50 nucleotide residues of SEQ ID NO:181 containing the EX17(a)15G, EX17(a)36C and EX17(a)87A. nucleotide variant EX18(a)690m (nucleotide residue Nos. 51-55 in SEQID NO:181), or a contiguous span of at least 0302) The present invention also encompasses an isolated 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 or 40 or nucleic acid comprising the nucleotide sequence of a region 50 nucleotide residues of SEQ ID NO:182 containing the of a RABEP1 genomic DNA or cDNA or mRNA, wherein nucleotide variant EX18(a)903m (nucleotide residue No. 51 the region contains one or more nucleotide variants as in SEQID NO:182), or a contiguous span of at least 18, 19. provided in Tables 19-23 (e.g., EX1(a)-551T, EX18(a)646m, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 or 40 or 50 EX18(a)690m, EX18(a)903m, EX18(a) 1689m and nucleotide residues of SEQ ID NO:185 containing the EX18(a)2373m), or one or more nucleotide variants that will nucleotide variant EX18(a) 1689m (nucleotide residue Nos. give rise to one or more amino acid variants of Tables 19-23, 51-55 in SEQID NO:185), or a contiguous span of at least or the complement thereof. Such regions can be isolated and 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 or 40 or analyzed to efficiently detect the nucleotide variants of the 50 nucleotide residues of SEQ ID NO:189 containing the present invention. Also, such regions can also be isolated nucleotide variant EX18(a)2373m (nucleotide residue No. and used as probes or primers in detection of the nucleotide 51 in SEQ ID NO:189), or the complements thereof. variants of the present invention and other uses as will be clear from the descriptions below. 0306 The present invention further provides an isolated TAP2 nucleic acid containing at least one of the newly 0303 Thus, in one embodiment, the isolated nucleic acid discovered nucleotide variants as Summarized in Table 24, comprises a contiguous span of at least 12, 15, 17, 18, 19. or one or more nucleotide variants that will result in the 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 50, 70 or 100 amino acid variants provided in Tables 24 and/or 25, e.g., nucleotide residues of a RABEP1 nucleic acid, the contigu EX12(a)356T, EX12(a)358m and EX12(a)1132m. The term ous span containing one or more nucleotide variants of “TAP2 nucleic acid' is as defined above and means a Tables 19-23 (e.g., EX1(a)-551T, EX18(a)646m, naturally existing nucleic acid coding for a wild-type or EX18(a)690m, EX18(a)903m, EX18(a) 1689m and variant or mutant TAP2. The term “TAP2 nucleic acid' is EX18(a)2373m), or the complement thereof. In specific inclusive and may be in the form of either double-stranded embodiments, the isolated nucleic acid are oligonucleotides or single-stranded nucleic acids, and a single Strand can be having a contiguous span of from about 17, 18, 19, 20, 21, either of the two complementing strands. The isolated TAP2 22, 23 or 25 to about 30, 40 or 50, preferably from about 21 nucleic acid can be naturally existing genomic DNA, mRNA to about 30 nucleotide residues, of any RABEP1 nucleic or cDNA. In one embodiment, the isolated TAP2 nucleic acid, said contiguous span containing one or more nucle acid has a nucleotide sequence according to SEQID NO:202 otide variants of Tables 19-23 (e.g., EX1(a)-551T, but containing one or more exonic nucleotide variants of EX18(a)646m, EX18(a690m, EX18(a)903m, EX18(a) 1689m Tables 24 and/or 25 (e.g., EX11(a)17G, EX12(a)61G, and EX18(a)2373m). EX12(a) 127C and EX12(a)159T), or the complement 0304. In one embodiment, the isolated nucleic acid com thereof. prises a contiguous span of at least 12, 15, 17, 18, 19, 20, 21. 0307. In another embodiment, the isolated TAP2 nucleic 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 50, 70 or 100 acid has a nucleotide sequence that is at least 95%, prefer nucleotide residues of any one of SEQ ID NOs: 172-196, ably at least 97% and more preferably at least 99% identical containing one or more nucleotide variants of Tables 19-23 to SEQ ID NO:202 but contains one or more exonic nucle (e.g., EX1(a)-551T, EX18(a)646m, EX18(a)690m, otide variants of Tables 24 and/or 25 (e.g., EX11(a) 17G, EX18(a)903m, EX18(a) 1689m and EX18(a)2373m), or the EX12(a)61G, EX12(a)127C and EX12(a)159T), or one or complement thereof. In specific embodiments, the isolated more nucleotide variants that will result in one or more nucleic acid comprises a nucleotide sequence according to amino acid variants of Tables 24 and/or 25, or the comple any one of SEQ ID NOs: 172-196. In preferred embodi ment thereof. ments, the isolated nucleic acid are oligonucleotides having a contiguous span of from about 17, 18, 19, 20, 21, 22, 23 0308). In yet another embodiment, the isolated TAP2 or 25 to about 30, 40 or 50, preferably from about 21 to nucleic acid has a nucleotide sequence encoding TAP2 about 30 nucleotide residues, of any one of SEQ ID protein having an amino acid sequence according to SEQID NOs: 172-196 and containing one or more nucleotide vari NO:203 but contains one or more amino acid variants of ants of Tables 19-23 (e.g., EX1(a)-551T, EX18(a)646m, Tables 24 and/or 25 (e.g., EX12(a) 19T and EX12(a)61G). EX18(a)690m, EX18(a)903m, EX18(a) 1689m and Isolated TAP2 nucleic acids having a nucleotide sequence EX18(a)2373m). The complements of the isolated nucleic that is the complement of the sequence are also encom acids are also encompassed by the present invention. passed by the present invention. 0309. In yet another embodiment, the isolated TAP2 0305 Thus, for example, an isolated nucleic acid of the nucleic acid has a nucleotide sequence encoding a TAP2 present invention can have a contiguous span of at least 18, protein having an amino acid sequence that is at least 95%, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 or 40 or 50 nucleotide residues of SEQ ID NO:172 containing the preferably at least 97% and more preferably at least 99% nucleotide variant EX1(a)-551T (nucleotide residue No. 51 identical to SEQID NO:203 but contains one or more amino in SEQID NO:172), or a contiguous span of at least 18, 19. acid variants of Tables 24 and/or 25 (e.g., EX12(a) 19T and 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 or 40 or 50 EX12(a)61G), or the complement thereof. nucleotide residues of SEQ ID NO:180 containing the 0310. The present invention also provides an isolated nucleotide variant EX18(a)646m (nucleotide residue Nos. nucleic acid, naturally occurring or artificial, having a nucle US 2007/0O82347 A1 Apr. 12, 2007

otide sequence that is at least 95%, preferably at least 97% nucleotide variants of the present invention and other uses as and more preferably at least 99% identical to SEQ ID will be clear from the descriptions below. NO:202 except for containing one or more nucleotide vari ants of Tables 24 and/or 25 (e.g., EX11(a) 17G, EX12(a)61G, 0318. Thus, in one embodiment, the isolated nucleic acid EX12(a) 127C and EX12(a)159T), or the complement comprises a contiguous span of at least 12, 15, 17, 18, 19. thereof. 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 50, 70 or 100 nucleotide residues of a TAP2 nucleic acid, the contiguous 0311. In another embodiment, the present invention pro span containing one or more nucleotide variants of Tables 24 vides an isolated nucleic acid, naturally occurring or artifi and/or 25 (e.g., EX12(a)356T, EX12(a)358m and cial, having a nucleotide sequence encoding a TAP2 protein EX12(a) 1132m), or the complement thereof. In specific having an amino acid sequence according to SEQ ID embodiments, the isolated nucleic acid are oligonucleotides NO:203 but containing one or more amino acid variants of having a contiguous span of from about 17, 18, 19, 20, 21. Tables 24 and/or 25 (e.g., EX12(a) 19T and EX12(a)61G). 22, 23 or 25 to about 30, 40 or 50, preferably from about 21 Isolated nucleic acids having a nucleotide sequence that is to about 30 nucleotide residues, of any TAP2 nucleic acid, the complement of the sequence are also encompassed by said contiguous span containing one or more nucleotide the present invention. variants of Tables 24 and/or 25 (e.g., EX12(a)356T, 0312. In addition, isolated nucleic acids are also provided EX12(a)358m and EX12(a)1132m). which have a nucleotide sequence encoding a protein having 0319. In one embodiment, the isolated nucleic acid com an amino acid sequence that is at least 95%, preferably at prises a contiguous span of at least 12, 15, 17, 18, 19, 20, 21. least 97% and more preferably at least 99% identical to SEQ 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 50, 70 or 100 ID NO:203 but containing one or more amino acid variants nucleotide residues of any one of SEQ ID NOS:206-227, of Tables 24 and/or 25 (e.g., EX12(a) 19T and EX12(a)61G), containing one or more nucleotide variants of Tables 24 or the complement thereof. and/or 25 (e.g., EX12(a)356T, EX12(a)358m and EX12(a) 1132m), or the complement thereof. In specific 0313 Also encompassed are isolated TAP2 nucleic acids embodiments, the isolated nucleic acid comprises a nucle obtainable by: otide sequence according to any one of SEQ ID NOs: (a) providing a human genomic library; 206-227. In preferred embodiments, the isolated nucleic acid are oligonucleotides having a contiguous span of from about (b) screening the genomic library using a probe having a 17, 18, 19, 20, 21, 22, 23 or 25 to about 30, 40 or 50, nucleotide sequence according to any one of SEQ ID preferably from about 21 to about 30 nucleotide residues, of NOs:202, 204, 206-227; and any one of SEQ ID NOS: 206-227 and containing one or 0314 (c) producing a genomic DNA comprising a con more nucleotide variants of Tables 24 and/or 25 (e.g., tiguous span of at least 30 nucleotides of any one of SEQID EX12(a)356T, EX12(a)358m and EX12(a)1132m). The NOs: 202, 204, 206-227, wherein the genomic DNA thus complements of the isolated nucleic acids are also encom produced contains one or more of the SNPs of the present passed by the present invention. invention in Tables 24 and/or 25, such as EX12(a)356T. 0320 Thus, for example, an isolated nucleic acid of the EX12(a)358m and EX12(a)1132m. present invention can have a contiguous span of at least 18, 0315. The present invention also includes isolated TAP2 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 or 40 or 50 nucleic acids obtainable by: nucleotide residues of SEQ ID NO:212 containing the nucleotide variant EX12(a)356T (nucleotide residue No. 51 (i) providing a cDNA library using human mRNA from a in SEQID NO:212), or a contiguous span of at least 18, 19. human tissue, e.g., blood; 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 or 40 or 50 (ii) screening the cDNA library using a probe having a nucleotide residues of SEQ ID NO:217 containing the nucleotide variant, EX12(a)358m (nucleotide residue No. nucleotide sequence according to any one of SEQ ID Nos: 51-60 in SEQID NO:217), or a contiguous span of at least 202, 204, 206-227; and 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 or 40 or 0316 (iii) producing a cDNA DNA comprising a con 50 nucleotide residues of SEQ ID NO:225 containing the tiguous span of at least 30 nucleotides of any one of SEQID nucleotide variant and EX12(a) 1132m (nucleotide residue NOs: 202, 204, 206-227, wherein the cDNA thus produced No. 51-226 in SEQ ID NO:225), or the complements contains one or more of the SNPs of the present invention in thereof. Tables 24 and/or 25, such as EX12(a)356T, EX12(a)358m 0321) The present invention further provides an isolated and EX12(a)1132m. NARG2 nucleic acid containing at least one of the newly 0317. The present invention also encompasses an isolated discovered nucleotide variants as summarized in Table 26, nucleic acid comprising the nucleotide sequence of a region or one or more nucleotide variants that will result in the of a TAP2 genomic DNA or cDNA or mRNA, wherein the amino acid variants provided in Table 26, e.g., EX14(a)+ region contains one or more nucleotide variants as provided 15C, EX16(a) 1757m, EX16(a)2306G, EX16(a)2547G and in Tables 24 and/or 25 (e.g., EX12(a)356T, EX12(a)358m EX16(a)4025m. The term “NARG2 nucleic acid” is as and EX12(a) 1132m), or one or more nucleotide variants that defined above and means a naturally existing nucleic acid will give rise to one or more amino acid variants of Tables coding for a wild-type or variant or mutant NARG2. The 24 and/or 25, or the complement thereof. Such regions can term "NARG2 nucleic acid' is inclusive and may be in the be isolated and analyzed to efficiently detect the nucleotide form of either double-stranded or single-stranded nucleic variants of the present invention. Also, such regions can also acids, and a single strand can be either of the two comple be isolated and used as probes or primers in detection of the menting strands. The isolated NARG2 nucleic acid can be US 2007/0O82347 A1 Apr. 12, 2007 32 naturally existing genomic DNA, mRNA or cDNA. In one amino acid variants of Table 26, or the complement thereof. embodiment, the isolated NARG2 nucleic acid has a nucle Such regions can be isolated and analyzed to efficiently otide sequence according to SEQID NO:230 but containing detect the nucleotide variants of the present invention. Also, one or more exonic nucleotide variants of Table 26 (e.g., Such regions can also be isolated and used as probes or EX12(a)48C), or the complement thereof. primers in detection of the nucleotide variants of the present 0322. In another embodiment, the isolated NARG2 invention and other uses as will be clear from the descrip nucleic acid has a nucleotide sequence that is at least 95%, tions below. preferably at least 97% and more preferably at least 99% identical to SEQID NO:230 but contains one or more exonic 0330 Thus, in one embodiment, the isolated nucleic acid nucleotide variants of Table 26 (e.g., EX12(a)48C), or one or comprises a contiguous span of at least 12, 15, 17, 18, 19. more nucleotide variants that will result in one or more 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 50, 70 or 100 amino acid variants of Table 26, or the complement thereof. nucleotide residues of a NARG2 nucleic acid, the contigu ous span containing one or more nucleotide variants of Table 0323 In yet another embodiment, the isolated NARG2 26 (e.g., EX14(a)+15C, EX16(a)1757m, EX16(a)2306G, nucleic acid has a nucleotide sequence encoding NARG2 EX16(a)2547G and EX16(a)4025m), or the complement protein having an amino acid sequence according to SEQID thereof. In specific embodiments, the isolated nucleic acid NO:231 but contains one or more amino acid variants of are oligonucleotides having a contiguous span of from about Table 26 (e.g., EX12(a)48C). Isolated NARG2 nucleic acids 17, 18, 19, 20, 21, 22, 23 or 25 to about 30, 40 or 50, having a nucleotide sequence that is the complement of the preferably from about 21 to about 30 nucleotide residues, of sequence are also encompassed by the present invention. any NARG2 nucleic acid, said contiguous span containing 0324. The present invention also provides an isolated one or more nucleotide variants of Table 26 (e.g., EX14(a)+ nucleic acid, naturally occurring or artificial, having a nucle 15C, EX16(a) 1757m, EX16(a)2306G, EX16(a)2547G and otide sequence that is at least 95%, preferably at least 97% EX16(a)4025m). and more preferably at least 99% identical to SEQ ID NO:230 except for containing one or more nucleotide vari 0331 In one embodiment, the isolated nucleic acid com ants of Table 26 (e.g., EX12(a)48C), or the complement prises a contiguous span of at least 12, 15, 17, 18, 19, 20, 21. thereof. 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 50, 70 or 100 nucleotide residues of any one of SEQ ID NOS:232-238, 0325 Also encompassed are isolated NARG2 nucleic containing one or more nucleotide variants of Table 26 (e.g., acids obtainable by: EX14(a)+15C, EX16(a) 1757m, EX16(a)2306G, (a) providing a human genomic library; EX16(a)2547G and EX16(a)4025m), or the complement (b) screening the genomic library using a probe having a thereof. In specific embodiments, the isolated nucleic acid nucleotide sequence according to any one of SEQ ID comprises a nucleotide sequence according to any one of SEQ ID NOs: 232-238. In preferred embodiments, the NOs:230, 232-238; and isolated nucleic acid are oligonucleotides having a contigu 0326 (c) producing a genomic DNA comprising a con ous span of from about 17, 18, 19, 20, 21, 22, 23 or 25 to tiguous span of at least 30 nucleotides of any one of SEQID about 30, 40 or 50, preferably from about 21 to about 30 NOs: 230, 232-238, wherein the genomic DNA thus pro nucleotide residues, of any one of SEQ ID NOs: 232-238 duced contains one or more of the SNPs of the present and containing one or more nucleotide variants of Table 26 invention in Table 26, such as EX14(a)+15C, (e.g., EX14(a)+15C, EX16(a)1757m, EX16(a)2306G, EX16(a) 1757m, EX16(a)2306G, EX16(a)2547G and EX16(a)2547G and EX16(a)4025m). The complements of EX16(a)4025m. the isolated nucleic acids are also encompassed by the 0327. The present invention also includes isolated present invention. NARG2 nucleic acids obtainable by: 0332 Thus, for example, an isolated nucleic acid of the (i) providing a cDNA library using human mRNA from a present invention can have a contiguous span of at least 18, human tissue, e.g., blood; 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 or 40 or 50 nucleotide residues of SEQ ID NO:234 containing the (ii) screening the cDNA library using a probe having a nucleotide variant EX14(a)+15C (nucleotide residue No. 51 nucleotide sequence according to any one of SEQ ID NOS in SEQID NO:234), or a contiguous span of at least 18, 19. 230, 232-238; and 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 or 40 or 50 nucleotide residues of SEQ ID NO:235 containing the 0328 (iii) producing a cDNA DNA comprising a con nucleotide variant EX16(a) 1757m (nucleotide residue No. tiguous span of at least 30 nucleotides of any one of SEQID 51 in SEQID NO:235), or a contiguous span of at least 18, NOs: 230, 232-238, wherein the cDNA thus produced 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 or 40 or 50 contains one or more of the SNPs of the present invention in nucleotide residues of SEQ ID NO:237 containing the Table 26, such as EX12(a)48C. nucleotide variant EX16(a)2547G (nucleotide residue No. 51 0329. The present invention also encompasses an isolated in SEQID NO:237), or a contiguous span of at least 18, 19. nucleic acid comprising the nucleotide sequence of a region 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 or 40 or 50 of a NARG2 genomic DNA or cDNA or mRNA, wherein the nucleotide residues of SEQ ID NO:236 containing the region contains one or more nucleotide variants as provided nucleotide variant EX16(a)2306G (nucleotide residue Nos. in Table 26 (e.g., EX14(a)+15C, EX16(a) 1757m, 51, 52 and 53 in SEQ ID NO:236), or a contiguous span of EX16(a)2306G, EX16(a)2547G and EX16(a)4025m), or one at least 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 or more nucleotide variants that will give rise to one or more or 40 or 50 nucleotide residues of SEQID NO:238 contain US 2007/0O82347 A1 Apr. 12, 2007

ing the nucleotide variant EX16(a)4025m (nucleotide resi 0340 Also encompassed are isolated DDX58 nucleic due Nos. 51, 52, 53, 54 and 55 in SEQ ID NO:238), or the acids obtainable by: complements thereof. (a) providing a human genomic library; 0333. The present invention further provides an isolated DDX58 nucleic acid containing at least one of the newly (b) screening the genomic library using a probe having a discovered nucleotide variants as summarized in Table 27, nucleotide sequence according to any one of SEQ ID NOs: or one or more nucleotide variants that will result in the 274, 276, 277; and amino acid variants provided in Table 27. The term “DDX58 (c) producing a genomic DNA comprising a contiguous span nucleic acid is as defined above and means a naturally of at least 30 nucleotides of any one of SEQ ID NOS: 274, existing nucleic acid coding for a wild-type or variant or 276, 277, wherein the genomic DNA thus produced contains mutant DDX58. The term “DDX58 nucleic acid is inclu one or more of the SNPs of the present invention in Table 27. sive and may be in the form of either double-stranded or single-stranded nucleic acids, and a single strand can be 0341 The present invention also includes isolated either of the two complementing strands. The isolated DDX58 nucleic acids obtainable by: DDX58 nucleic acid can be naturally existing genomic DNA, mRNA or cDNA. In one embodiment, the isolated (i) providing a cDNA library using human mRNA from a DDX58 nucleic acid has a nucleotide sequence according to human tissue, e.g., blood; SEQ ID NO:274 but containing one or more exonic nucle (ii) screening the cDNA library using a probe having a otide variants of Table 27 (e.g., EX17(a)63), or the comple nucleotide sequence according to any one of SEQ ID NOs: ment thereof. 274, 276, 277; and 0334) In another embodiment, the isolated DDX58 (iii) producing a cDNA DNA comprising a contiguous span nucleic acid has a nucleotide sequence that is at least 95%, of at least 30 nucleotides of any one of SEQ ID NOS: 274, preferably at least 97% and more preferably at least 99% 276, 277, wherein the cDNA thus produced contains one or identical to SEQID NO:274 but contains one or more exonic more of the variants of the present invention in Table 27. nucleotide variants of Table 27, or one or more nucleotide variants that will result in one or more amino acid variants 0342. The present invention also encompasses an isolated of Table 27, or the complement thereof. nucleic acid comprising the nucleotide sequence of a region of a DDX58 genomic DNA or cDNA or mRNA, wherein the 0335) In yet another embodiment, the isolated DDX58 region contains one or more nucleotide variants as provided nucleic acid has a nucleotide sequence encoding DDX58 in Table 27, or one or more nucleotide variants that will give protein having an amino acid sequence according to SEQID rise to one or more amino acid variants of Tables 27, or the NO:275 but contains one or more amino acid variants of complement thereof. Such regions can be isolated and Table 27. Isolated DDX58 nucleic acids having a nucleotide analyzed to efficiently detect the nucleotide variants of the sequence that is the complement of the sequence are also present invention. Also, such regions can also be isolated encompassed by the present invention. and used as probes or primers in detection of the nucleotide 0336. In yet another embodiment, the isolated DDX58 variants of the present invention and other uses as will be nucleic acid has a nucleotide sequence encoding a DDX58 clear from the descriptions below. protein having an amino acid sequence that is at least 95%, 0343 Thus, in one embodiment, the isolated nucleic acid preferably at least 97% and more preferably at least 99% comprises a contiguous span of at least 12, 15, 17, 18, 19. identical to SEQID NO:275 but contains one or more amino 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 50, 70 or 100 acid variants of Table 27, or the complement thereof. nucleotide residues of a DDX58 nucleic acid, the contiguous 0337 The present invention also provides an isolated span containing one or more nucleotide variants selected nucleic acid, naturally occurring or artificial, having a nucle from those in Table 27, or the complement thereof. In otide sequence that is at least 95%, preferably at least 97% specific embodiments, the isolated nucleic acids are oligo and more preferably at least 99% identical to SEQ ID nucleotides having a contiguous span of from about 17, 18, NO:274 except for containing one or more nucleotide vari 19, 20, 21, 22, 23 or 25 to about 30, 40 or 50, preferably ants of Table 27, or the complement thereof. from about 21 to about 30 nucleotide residues, of any DDX58 nucleic acid, said contiguous span containing one or 0338. In another embodiment, the present invention pro more nucleotide variants of Table 27. vides an isolated nucleic acid, naturally occurring or artifi cial, having a nucleotide sequence encoding a DDX58 0344) In one embodiment, the isolated nucleic acid com protein having an amino acid sequence according to SEQID prises a contiguous span of at least 12, 15, 17, 18, 19, 20, 21. NO:275 but containing one or more amino acid variants of 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 50, 70 or 100 Table 27. Isolated nucleic acids having a nucleotide nucleotide residues of any one of SEQ ID NOS:276-277, sequence that is the complement of the sequence are also containing one or more nucleotide variants of Tables 27, or encompassed by the present invention. the complement thereof. In specific embodiments, the iso lated nucleic acid comprises a nucleotide sequence accord 0339. In addition, isolated nucleic acids are also provided ing to any one of SEQ ID NOS:276-277. In preferred which have a nucleotide sequence encoding a protein having embodiments, the isolated nucleic acids are oligonucleotides an amino acid sequence that is at least 95%, preferably at having a contiguous span of from about 17, 18, 19, 20, 21. least 97% and more preferably at least 99% identical to SEQ 22, 23 or 25 to about 30, 40 or 50, preferably from about 21 ID NO:275 but containing one or more amino acid variants to about 30 nucleotide residues, of any one of SEQ ID of Table 27, or the complement thereof. NOs:276-277 and containing one or more nucleotide vari US 2007/0O82347 A1 Apr. 12, 2007 34 ants of Tables 27. The complements of the isolated nucleic NO:244 but containing one or more amino acid variants of acids are also encompassed by the present invention. Table 28 and/or Table 29. Isolated nucleic acids having a 0345 Thus, for example, an isolated nucleic acid of the nucleotide sequence that is the complement of the sequence present invention can have a contiguous span of at least 18, are also encompassed by the present invention. 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 or 40 or 50 0352. In addition, isolated nucleic acids are also provided nucleotide residues of SEQ ID NO:276 containing the which have a nucleotide sequence encoding a protein having nucleotide variant EX14(a)+78 (nucleotide residue No. 51 in an amino acid sequence that is at least 95%, preferably at SEQID NO:276), or a contiguous span of at least 18, 19, 20, least 97% and more preferably at least 99% identical to SEQ 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 or 40 or 50 nucleotide ID NO:244 but containing one or more amino acid variants residues of SEQ ID NO:277 containing the nucleotide of Table 28 and/or Table 29, or the complement thereof. variant EX17(a)63 (nucleotide residue No. 51 in SEQ ID NO:277, or the complements thereof. 0353 Also encompassed are isolated CD39 nucleic acids obtainable by: 0346) The present invention further provides an isolated CD39 nucleic acid containing at least one of the newly (a) providing a human genomic library; discovered nucleotide variants as summarized in Table 28, or one or more nucleotide variants that will result in the (b) screening the genomic library using a probe having a amino acid variants provided in Tables 28 and/or 29. The nucleotide sequence according to any one of SEQ ID NOs: term “CD39 nucleic acid' is as defined above and means a 244, 246, 247; and naturally existing nucleic acid coding for a wild-type or 0354 (c) producing a genomic DNA comprising a con variant or mutant CD39. The term “CD39 nucleic acid is tiguous span of at least 30 nucleotides of any one of SEQID inclusive and may be in the form of either double-stranded or single-stranded nucleic acids, and a single Strand can be NOs: 244, 246, 247, wherein the genomic DNA thus pro either of the two complementing strands. The isolated CD39 duced contains one or more of the SNPs of the present nucleic acid can be naturally existing genomic DNA, mRNA invention in Table 28 and/or Table 29. or cDNA. In one embodiment, the isolated CD39 nucleic 0355 The present invention also includes isolated CD39 acid has a nucleotide sequence according to SEQID NO:243 nucleic acids obtainable by: but containing one or more exonic nucleotide variants of Table 28 and/or 29 (e.g., EX17(a)63), or the complement (i) providing a cDNA library using human mRNA from a thereof. human tissue, e.g., blood; 0347 In another embodiment, the isolated CD39 nucleic (ii) screening the cDNA library using a probe having a acid has a nucleotide sequence that is at least 95%, prefer nucleotide sequence according to any one of SEQ ID NOs: ably at least 97% and more preferably at least 99% identical 244, 246, 247; and to SEQ ID NO:243, but contains one or more exonic nucleotide variants of Table 28 and/or Table 29, or one or 0356 (iii) producing a cDNA DNA comprising a con more nucleotide variants that will result in one or more tiguous span of at least 30 nucleotides of any one of SEQID amino acid variants of Table 28 and/or Table 29, or the NOs: 244, 246, 247, wherein the cDNA thus produced complement thereof. contains one or more of the variants of the present invention in Table 28 and/or Table 29. 0348. In yet another embodiment, the isolated CD39 nucleic acid has a nucleotide sequence encoding CD39 0357 The present invention also encompasses an isolated protein having an amino acid sequence according to SEQID nucleic acid comprising the nucleotide sequence of a region NO:244 but contains one or more amino acid variants of of a CD39 genomic DNA or cDNA or mRNA, wherein the Table 29 and/or Table 29. Isolated CD39 nucleic acids region contains one or more nucleotide variants as provided having a nucleotide sequence that is the complement of the in Tables 1 and 2, or one or more nucleotide variants that will sequence are also encompassed by the present invention. give rise to one or more amino acid variants of Table 28 and/or Table 29, or the complement thereof. Such regions 0349. In yet another embodiment, the isolated CD39 can be isolated and analyzed to efficiently detect the nucle nucleic acid has a nucleotide sequence encoding a CD39 otide variants of the present invention. Also, such regions protein having an amino acid sequence that is at least 95%, can also be isolated and used as probes or primers in preferably at least 97% and more preferably at least 99% detection of the nucleotide variants of the present invention identical to SEQID NO:244 but contains one or more amino acid variants of Table 28 and/or Table 29, or the complement and other uses as will be clear from the descriptions below. thereof. 0358 Thus, in one embodiment, the isolated nucleic acid comprises a contiguous span of at least 12, 15, 17, 18, 19. 0350. The present invention also provides an isolated 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 50, 70 or 100 nucleic acid, naturally occurring or artificial, having a nucle nucleotide residues of a CD39 nucleic acid, the contiguous otide sequence that is at least 95%, preferably at least 97% span containing one or more nucleotide variants selected and more preferably at least 99% identical to SEQ ID from those in Tables 1 and 2, or the complement thereof. In NO:243 except for containing one or more nucleotide vari specific embodiments, the isolated nucleic acids are oligo ants of Table 28 and/or Table 29, or the complement thereof. nucleotides having a contiguous span of from about 17, 18, 0351. In another embodiment, the present invention pro 19, 20, 21, 22, 23 or 25 to about 30, 40 or 50, preferably vides an isolated nucleic acid, naturally occurring or artifi from about 21 to about 30 nucleotide residues, of any CD39 cial, having a nucleotide sequence encoding a CD39 protein nucleic acid, said contiguous span containing one or more having an amino acid sequence according to SEQ ID nucleotide variants of Table 28 and/or Table 29. US 2007/0O82347 A1 Apr. 12, 2007

0359. In one embodiment, the isolated nucleic acid com 0365. The present invention also provides an isolated prises a contiguous span of at least 12, 15, 17, 18, 19, 20, 21. nucleic acid, naturally occurring or artificial, having a nucle 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 50, 70 or 100 otide sequence that is at least 95%, preferably at least 97% nucleotide residues of any one of SEQ ID NOS:245-246, and more preferably at least 99% identical to SEQ ID containing one or more nucleotide variants of Table 28 NO:249 except for containing one or more nucleotide vari and/or Table 29, or the complement thereof. In specific ants of Table 30, or the complement thereof. embodiments, the isolated nucleic acid comprises a nucle otide sequence according to any one of SEQ ID NOs: 0366. In another embodiment, the present invention pro 245-246. In preferred embodiments, the isolated nucleic vides an isolated nucleic acid, naturally occurring or artifi acids are oligonucleotides having a contiguous span of from cial, having a nucleotide sequence encoding a FKBP1a about 17, 18, 19, 20, 21, 22, 23 or 25 to about 30, 40 or 50, protein having an amino acid sequence according to SEQID preferably from about 21 to about 30 nucleotide residues, of NO:250 but containing one or more amino acid variants of any one of SEQ ID NOS: 245–246 and containing one or Table 30. Isolated nucleic acids having a nucleotide more nucleotide variants of Table 28 and/or Table 29. The sequence that is the complement of the sequence are also complements of the isolated nucleic acids are also encom encompassed by the present invention. passed by the present invention. 0367. In addition, isolated nucleic acids are also provided 0360 Thus, for example, an isolated nucleic acid of the which have a nucleotide sequence encoding a protein having present invention can have a contiguous span of at least 18, an amino acid sequence that is at least 95%, preferably at 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 or 40 or 50 least 97% and more preferably at least 99% identical to SEQ nucleotide residues of SEQ ID NO:245 containing the ID NO:250 but containing one or more amino acid variants nucleotide variant EX4(a)-10 (nucleotide residue No. 51 in of Table 30, or the complement thereof. SEQID NO:245), or a contiguous span of at least 18, 19, 20, 0368. Also encompassed are isolated FKBP1 a nucleic 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 or 40 or 50 nucleotide acids obtainable by: residues of SEQ ID NO:246 containing the nucleotide variant EX10(a)3061 (nucleotide residue No. 51 in SEQ ID (a) providing a human genomic library; NO:246), or the complements thereof. (b) screening the genomic library using a probe having a 0361 Accordingly, the present invention provides an nucleotide sequence according to any one of SEQ ID isolated FKBP1 a nucleic acid containing at least one of the NOS:249, 251; and newly discovered nucleotide variants as Summarized in Table 30, or one or more nucleotide variants that will result (c) producing a genomic DNA comprising a contiguous span in the amino acid variants provided in Table 30. The term of at least 30 nucleotides of any one of SEQ ID NOs: 249, “FKBP1 a nucleic acid' is as defined above and means a 251, wherein the genomic DNA thus produced contains one naturally existing nucleic acid coding for a wild-type or or more of the SNPs of the present invention in Table 30. variant or mutant FKBP1a. The term “FKBP1 a nucleic acid 0369 The present invention also includes isolated is inclusive and may be in the form of either double-stranded FKBP1a nucleic acids obtainable by: or single-stranded nucleic acids, and a single Strand can be either of the two complementing strands. The isolated (i) providing a cDNA library using human mRNA from a FKBP1a nucleic acid can be naturally existing genomic human tissue, e.g., blood; DNA, mRNA or cDNA. In one embodiment, the isolated (ii) screening the cDNA library using a probe having a FKBP1a nucleic acid has a nucleotide sequence according to nucleotide sequence according to any one of SEQ ID SEQ ID NO:249 but containing one or more exonic nucle NOS:249, 251; and otide variants of Table 30 (e.g., EX5(a)8A), or the comple ment thereof. (iii) producing a cDNA DNA comprising a contiguous span 0362. In another embodiment, the isolated FKBP1a of at least 30 nucleotides of any one of SEQ ID NOS:249, nucleic acid has a nucleotide sequence that is at least 95%, 251, wherein the cDNA thus produced contains one or more preferably at least 97% and more preferably at least 99% of the variants of the present invention in Table 30. identical to SEQID NO:249 but contains one or more exonic 0370. The present invention also encompasses an isolated nucleotide variants of Table 30, or one or more nucleotide nucleic acid comprising the nucleotide sequence of a region variants that will result in one or more amino acid variants of a FKBP1a genomic DNA or cDNA or mRNA, wherein of Table 30, or the complement thereof. the region contains one or more nucleotide variants as 0363. In yet another embodiment, the isolated FKBP1a provided in Table 30, or one or more nucleotide variants that nucleic acid has a nucleotide sequence encoding FKBP1a will give rise to one or more amino acid variants of Table 30, protein having an amino acid sequence according to SEQID or the complement thereof. Such regions can be isolated and NO:250 but contains one or more amino acid variants of analyzed to efficiently detect the nucleotide variants of the Table 30. Isolated FKBP1 a nucleic acids having a nucleotide present invention. Also, such regions can also be isolated sequence that is the complement of the sequence are also and used as probes or primers in detection of the nucleotide encompassed by the present invention. variants of the present invention and other uses as will be 0364. In yet another embodiment, the isolated FKBP1a clear from the descriptions below. nucleic acid has a nucleotide sequence encoding a FKBP1a 0371 Thus, in one embodiment, the isolated nucleic acid protein having an amino acid sequence that is at least 95%, comprises a contiguous span of at least 12, 15, 17, 18, 19. preferably at least 97% and more preferably at least 99% 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 50, 70 or 100 identical to SEQID NO:250 but contains one or more amino nucleotide residues of a FKBP1 a nucleic acid, the contigu acid variants of Table 30, or the complement thereof. ous span containing one or more nucleotide variants selected US 2007/0O82347 A1 Apr. 12, 2007 36 from those in Table 30, or the complement thereof. In preferably at least 97% and more preferably at least 99% specific embodiments, the isolated nucleic acids are oligo identical to SEQID NO:254 but contains one or more amino nucleotides having a contiguous span of from about 17, 18, acid variants of Table 31, or the complement thereof. 19, 20, 21, 22, 23 or 25 to about 30, 40 or 50, preferably 0378. The present invention also provides an isolated from about 21 to about 30 nucleotide residues, of any nucleic acid, naturally occurring or artificial, having a nucle FKBP1a nucleic acid, said contiguous span containing one otide sequence that is at least 95%, preferably at least 97% or more nucleotide variants of Table 30. and more preferably at least 99% identical to SEQ ID 0372. In one embodiment, the isolated nucleic acid com NO:253 except for containing one or more nucleotide vari prises a contiguous span of at least 12, 15, 17, 18, 19, 20, 21. ants of Table 31, or the complement thereof. 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 50, 70 or 100 0379. In another embodiment, the present invention pro nucleotide residues of any one of SEQID NO:251, contain vides an isolated nucleic acid, naturally occurring or artifi ing one or more nucleotide variants of Table 30, or the cial, having a nucleotide sequence encoding a SRI protein complement thereof. In specific embodiments, the isolated having an amino acid sequence according to SEQ ID nucleic acid comprises a nucleotide sequence according to NO:254 but containing one or more amino acid variants of any one of SEQ ID NO:251. In preferred embodiments, the Table 31. Isolated nucleic acids having a nucleotide isolated nucleic acids are oligonucleotides having a contigu sequence that is the complement of the sequence are also ous span of from about 17, 18, 19, 20, 21, 22, 23 or 25 to encompassed by the present invention. about 30, 40 or 50, preferably from about 21 to about 30 nucleotide residues, of any one of SEQ ID NO:251 and 0380. In addition, isolated nucleic acids are also provided containing one or more nucleotide variants of Table 30. The which have a nucleotide sequence encoding a protein having complements of the isolated nucleic acids are also encom an amino acid sequence that is at least 95%, preferably at passed by the present invention. least 97% and more preferably at least 99% identical to SEQ ID NO:254 but containing one or more amino acid variants 0373 Thus, for example, an isolated nucleic acid of the of Table 31, or the complement thereof. present invention can have a contiguous span of at least 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 or 40 or 50 0381 Also encompassed are isolated SRI nucleic acids nucleotide residues of SEQ ID NO:251 containing the obtainable by: nucleotide variant EX5(a)8A (nucleotide residue No. 51 in (a) providing a human genomic library; SEQ ID NO:251), or the complements thereof. (b) screening the genomic library using a probe having a 0374. The present invention further provides an isolated nucleotide sequence according to any one of SEQ ID SRI nucleic acid containing at least one of the newly NO:253, 255; and discovered nucleotide variants as summarized in Tables 1 and 2, or one or more nucleotide variants that will result in (c) producing a genomic DNA comprising a contiguous span the amino acid variants provided in Table 31. The term “SRI of at least 30 nucleotides of any one of SEQ ID NOS:253, nucleic acid is as defined above and means a naturally 255, wherein the genomic DNA thus produced contains one existing nucleic acid coding for a wild-type or variant or or more of the SNPs of the present invention in Table 31. mutant SRI. The term "SRI nucleic acid' is inclusive and 0382. The present invention also includes isolated SRI may be in the form of either double-stranded or single nucleic acids obtainable by: Stranded nucleic acids, and a single strand can be either of the two complementing strands. The isolated SRI nucleic (i) providing a cDNA library using human mRNA from a acid can be naturally existing genomic DNA, mRNA or human tissue, e.g., blood; cDNA. In one embodiment, the isolated SRI nucleic acid has (ii) screening the cDNA library using a probe having a a nucleotide sequence according to SEQ ID NO:253 but nucleotide sequence according to any one of SEQ ID containing one or more exonic nucleotide variants of Table NO:253, 255; and 31 (e.g., EX9(a)351), or the complement thereof. (iii) producing a cDNA DNA comprising a contiguous span 0375. In another embodiment, the isolated SRI nucleic of at least 30 nucleotides of any one of SEQ ID NO:253, acid has a nucleotide sequence that is at least 95%, prefer 255, wherein the cDNA thus produced contains one or more ably at least 97% and more preferably at least 99% identical of the variants of the present invention in Table 31. to SEQ ID NO:253 but contains one or more exonic nucle otide variants of Table 31, or one or more nucleotide variants 0383. The present invention also encompasses an isolated that will result in one or more amino acid variants of Table nucleic acid comprising the nucleotide sequence of a region 31, or the complement thereof. of a SRI genomic DNA or cDNA or mRNA, wherein the region contains one or more nucleotide variants as provided 0376. In yet another embodiment, the isolated SRI in Table 31, or one or more nucleotide variants that will give nucleic acid has a nucleotide sequence encoding SRI protein rise to one or more amino acid variants of Table 31, or the having an amino acid sequence according to SEQ ID complement thereof. Such regions can be isolated and NO:254 but contains one or more amino acid variants of analyzed to efficiently detect the nucleotide variants of the Table 31. Isolated SRI nucleic acids having a nucleotide present invention. Also, such regions can also be isolated sequence that is the complement of the sequence are also and used as probes or primers in detection of the nucleotide encompassed by the present invention. variants of the present invention and other uses as will be 0377. In yet another embodiment, the isolated SRI clear from the descriptions below. nucleic acid has a nucleotide sequence encoding a SRI 0384 Thus, in one embodiment, the isolated nucleic acid protein having an amino acid sequence that is at least 95%, comprises a contiguous span of at least 12, 15, 17, 18, 19. US 2007/0O82347 A1 Apr. 12, 2007 37

20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 50, 70 or 100 protein having an amino acid sequence that is at least 95%, nucleotide residues of a SRI nucleic acid, the contiguous preferably at least 97% and more preferably at least 99% span containing one or more nucleotide variants selected identical to SEQID NO:258 but contains one or more amino from those in Table 31, or the complement thereof. In acid variants of Table 32, or the complement thereof. specific embodiments, the isolated nucleic acids are oligo nucleotides having a contiguous span of from about 17, 18, 0391 The present invention also provides an isolated 19, 20, 21, 22, 23 or 25 to about 30, 40 or 50, preferably nucleic acid, naturally occurring or artificial, having a nucle from about 21 to about 30 nucleotide residues, of any SRI otide sequence that is at least 95%, preferably at least 97% nucleic Table 31. and more preferably at least 99% identical to SEQ ID NO:257 except for containing one or more nucleotide vari 0385) In one embodiment, the isolated nucleic acid com ants of Table 32, or the complement thereof. prises a contiguous span of at least 12, 15, 17, 18, 19, 20, 21. 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 50, 70 or 100 0392. In another embodiment, the present invention pro nucleotide residues of SEQ ID NO: 255, containing one or vides an isolated nucleic acid, naturally occurring or artifi more nucleotide variants of Table 31, or the complement cial, having a nucleotide sequence encoding a XRRA1 thereof. In specific embodiments, the isolated nucleic acid protein having an amino acid sequence according to SEQID comprises a nucleotide sequence according to SEQ ID NO:258 but containing one or more amino acid variants of NO:253,255. In preferred embodiments, the isolated nucleic Table 32. Isolated nucleic acids having a nucleotide acids are oligonucleotides having a contiguous span of from sequence that is the complement of the sequence are also about 17, 18, 19, 20, 21, 22, 23 or 25 to about 30, 40 or 50, encompassed by the present invention. preferably from about 21 to about 30 nucleotide residues, of 0393. In addition, isolated nucleic acids are also provided SEQID NO:253,255 and containing one or more nucleotide which have a nucleotide sequence encoding a protein having variants of Table 31. The complements of the isolated an amino acid sequence that is at least 95%, preferably at nucleic acids are also encompassed by the present invention. least 97% and more preferably at least 99% identical to SEQ 0386 Thus, for example, an isolated nucleic acid of the ID NO:258 but containing one or more amino acid variants present invention can have a contiguous span of at least 18, of Table 32, or the complement thereof. 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 or 40 or 50 nucleotide residues of SEQ ID NO:255 containing the 0394 Also encompassed are isolated XRRA1 nucleic nucleotide variant EX9(a)351C (nucleotide residue No. 51 in acids obtainable by: SEQ ID NO:255), or the complements thereof. (a) providing a human genomic library; 0387 Accordingly, the present invention provides an (b) screening the genomic library using a probe having a isolated XRRA1 nucleic acid containing at least one of the nucleotide sequence according to any one of SEQ ID newly discovered nucleotide variants as Summarized in NOs:257, 259-263; and Table 32, or one or more nucleotide variants that will result in the amino acid variants provided in Table 32. The term (c) producing a genomic DNA comprising a contiguous span “XRRA1 nucleic acid' is as defined above and means a of at least 30 nucleotides of any one of SEQ ID NOS:257, naturally existing nucleic acid coding for a wild-type or 259-263, wherein the genomic DNA thus produced contains variant or mutant XRRA1. The term "XRRA1 nucleic acid one or more of the SNPs of the present invention in Table 32. is inclusive and may be in the form of either double-stranded or single-stranded nucleic acids, and a single Strand can be 0395. The present invention also includes isolated either of the two complementing strands. The isolated XRRA1 nucleic acids obtainable by: XRRA1 nucleic acid can be naturally existing genomic (i) providing a cDNA library using human mRNA from a DNA, mRNA or cDNA. In one embodiment, the isolated human tissue, e.g., blood; XRRA1 nucleic acid has a nucleotide sequence according to SEQ ID NO:257 but containing one or more exonic nucle (ii) screening the cDNA library using a probe having a otide variants of Table 32 (e.g., EX2(a)26, EX11(a).51 and nucleotide sequence according to any one of SEQ ID EX 13(a)62), or the complement thereof. NOs:257, 259-263; and 0388. In another embodiment, the isolated XRRA1 (iii) producing a cDNA DNA comprising a contiguous span nucleic acid has a nucleotide sequence that is at least 95%, of at least 30 nucleotides of any one of SEQ ID NOS:257, preferably at least 97% and more preferably at least 99% 259-263, wherein the cDNA thus produced contains one or identical to SEQID NO:257 but contains one or more exonic more of the variants of the present invention in Table 32. nucleotide variants of Table 32, or one or more nucleotide variants that will result in one or more amino acid variants 0396 The present invention also encompasses an isolated of Table 32, or the complement thereof. nucleic acid comprising the nucleotide sequence of a region of a XRRA1 genomic DNA or cDNA or mRNA, wherein the 0389. In yet another embodiment, the isolated XRRA1 region contains one or more nucleotide variants as provided nucleic acid has a nucleotide sequence encoding XRRA1 in Table 32, or one or more nucleotide variants that will give protein having an amino acid sequence according to SEQID rise to one or more amino acid variants of Table 32, or the NO:258 but contains one or more amino acid variants of complement thereof. Such regions can be isolated and Table 32. Isolated XRRA1 nucleic acids having a nucleotide analyzed to efficiently detect the nucleotide variants of the sequence that is the complement of the sequence are also present invention. Also, such regions can also be isolated encompassed by the present invention. and used as probes or primers in detection of the nucleotide 0390. In yet another embodiment, the isolated XRRA1 variants of the present invention and other uses as will be nucleic acid has a nucleotide sequence encoding a XRRA1 clear from the descriptions below. US 2007/0O82347 A1 Apr. 12, 2007

0397 Thus, in one embodiment, the isolated nucleic acid otide variants of Table 33 (e.g., EX6(a)91), or one or more comprises a contiguous span of at least 12, 15, 17, 18, 19. nucleotide variants that will result in one or more amino acid 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 50, 70 or 100 variants of Table 33, or the complement thereof. nucleotide residues of a XRRA1 nucleic acid, the contigu ous span containing one or more nucleotide variants selected 0402. The present invention also provides an isolated from those in Table 32, or the complement thereof. In nucleic acid, naturally occurring or artificial, having a nucle specific embodiments, the isolated nucleic acids are oligo otide sequence that is at least 95%, preferably at least 97% nucleotides having a contiguous span of from about 17, 18, and more preferably at least 99% identical to SEQ ID 19, 20, 21, 22, 23 or 25 to about 30, 40 or 50, preferably NO:280 except for containing one or more nucleotide vari from about 21 to about 30 nucleotide residues, of any ants of Table 33 (e.g., EX6(a)91), or the complement thereof. XRRA1 nucleic acid, said contiguous span containing one 0403. Also encompassed are isolated IRF5 nucleic acids or more nucleotide variants of Table 32. obtainable by: 0398. In one embodiment, the isolated nucleic acid com (a) providing a human genomic library; prises a contiguous span of at least 12, 15, 17, 18, 19, 20, 21. 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 50, 70 or 100 (b) screening the genomic library using a probe having a nucleotide residues of any one of SEQ ID NOS:259-263, nucleotide sequence according to any one of SEQ ID containing one or more nucleotide variants of Table 32, or NOs:280, 282-290; and the complement thereof. In specific embodiments, the iso 0404 (c) producing a genomic DNA comprising a con lated nucleic acid comprises a nucleotide sequence accord tiguous span of at least 30 nucleotides of any one of SEQID ing to any one of SEQ ID NOS:259-263. In preferred NOs:280, 282-290, wherein the genomic DNA thus pro embodiments, the isolated nucleic acids are oligonucleotides having a contiguous span of from about 17, 18, 19, 20, 21. duced contains one or more of the SNPs of the present 22, 23 or 25 to about 30, 40 or 50, preferably from about 21 invention in Table 33, such as EX1(a)-82m and EX6(a).91m. to about 30 nucleotide residues, of any one of SEQ ID 04.05 The present invention also includes isolated IRF5 NOs:259-263 and containing one or more nucleotide vari nucleic acids obtainable by: ants of Table 32. The complements of the isolated nucleic (i) providing a cDNA library using human mRNA from a acids are also encompassed by the present invention. human tissue, e.g., blood; 0399. Thus, for example, an isolated nucleic acid of the present invention can have a contiguous span of at least 18, (ii) screening the cDNA library using a probe having a 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 or 40 or 50 nucleotide sequence according to any one of SEQ ID nucleotide residues of SEQ ID NO:259 containing the NOs:280, 282-290; and nucleotide variant EX2(a)26C (nucleotide residue No. 51 in 0406 (iii) producing a cDNA DNA comprising a con SEQID NO:259), or a contiguous span of at least 18, 19, 20, tiguous span of at least 30 nucleotides of any one of SEQID 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 or 40 or 50 nucleotide NOs:280, 282-290, wherein the cDNA thus produced con residues of SEQ ID NO:261 containing the nucleotide tains one or more of the SNPs of the present invention in variant EX11(a)51C (nucleotide residue No. 51 in SEQ ID Table 33, such as EX6(a)91. NO:261), or a contiguous span of at least 18, 19, 20, 21, 22. 23, 24, 25, 26, 27, 28, 29, or 30 or 40 or 50 nucleotide 0407. The present invention also encompasses an isolated residues of SEQ ID NO:262 containing the nucleotide nucleic acid comprising the nucleotide sequence of a region variant EX13(a)62C (nucleotide residue No. 51 in SEQ ID of a IRF5 genomic DNA or cDNA or mRNA, wherein the NO:262), or the complements thereof. region contains one or more nucleotide variants as provided in Table 33 (e.g., EX1(a)-82m and EX6(a)91 m), or one or 0400. The present invention provides an isolated IRF5 more nucleotide variants that will give rise to one or more nucleic acid containing at least one of the newly discovered amino acid variants of Table 33, or the complement thereof. nucleotide variants as summarized in Table 33, or one or Such regions can be isolated and analyzed to efficiently more nucleotide variants that will result in the amino acid detect the nucleotide variants of the present invention. Also, variants provided in Table 1, e.g., EX1(a)-82m and Such regions can also be isolated and used as probes or EX6(a).91m. The term “IRF5 nucleic acid” is as defined primers in detection of the nucleotide variants of the present above and means a naturally existing nucleic acid coding for invention and other uses as will be clear from the descrip a wild-type or variant or mutant IRF5. The term “IRF5 tions below. nucleic acid is inclusive and may be in the form of either double-stranded or single-stranded nucleic acids, and a 0408. Thus, in one embodiment, the isolated nucleic acid single strand can be either of the two complementing comprises a contiguous span of at least 12, 15, 17, 18, 19. strands. The isolated IRF5 nucleic acid can be naturally 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 50, 70 or 100 existing genomic DNA, mRNA or cDNA. In one embodi nucleotide residues of a IRF5 nucleic acid, the contiguous ment, the isolated IRF5 nucleic acid has a nucleotide span containing one or more nucleotide variants of Table 33 sequence according to SEQID NO:280 but containing one (e.g., EX1(a)-82m and EX6(a).91 m), or the complement or more exonic nucleotide variants of Table 33 (e.g., thereof. In specific embodiments, the isolated nucleic acid EX6(a)91), or the complement thereof. are oligonucleotides having a contiguous span of from about 17, 18, 19, 20, 21, 22, 23 or 25 to about 30, 40 or 50, 04.01. In another embodiment, the isolated IRF5 nucleic preferably from about 21 to about 30 nucleotide residues, of acid has a nucleotide sequence that is at least 95%, prefer any IRF5 nucleic acid, said contiguous span containing one ably at least 97% and more preferably at least 99% identical or more nucleotide variants of Table 33 (e.g., EX1(a)-82m to SEQ ID NO:280 but contains one or more exonic nucle and EX6(a)91 m). US 2007/0O82347 A1 Apr. 12, 2007 39

04.09. In one embodiment, the isolated nucleic acid com Tables 34 and/or 35. Isolated AMFR nucleic acids having a prises a contiguous span of at least 12, 15, 17, 18, 19, 20, 21. nucleotide sequence that is the complement of the sequence 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 50, 70 or 100 are also encompassed by the present invention. nucleotide residues of any one of SEQ ID NOS:3-11, con taining one or more nucleotide variants of Table 33 (e.g., 0414. In yet another embodiment, the isolated AMFR EX1(a)-82m and EX6(a).91 m), or the complement thereof. In nucleic acid has a nucleotide sequence encoding a AMFR specific embodiments, the isolated nucleic acid comprises a protein having an amino acid sequence that is at least 95%, nucleotide sequence according to any one of SEQ ID preferably at least 97% and more preferably at least 99% NOs:282-290. In preferred embodiments, the isolated identical to SEQID NO:292 but contains one or more amino nucleic acid are oligonucleotides having a contiguous span acid variants of Tables 34 and/or 35, or the complement of from about 17, 18, 19, 20, 21, 22, 23 or 25 to about 30, thereof. 40 or 50, preferably from about 21 to about 30 nucleotide 0415. The present invention also provides an isolated residues, of any one of SEQID NOS: 282-290 and contain nucleic acid, naturally occurring or artificial, having a nucle ing one or more nucleotide variants of Table 33 (e.g., otide sequence that is at least 95%, preferably at least 97% EX1(a)-82m and EX6(a)91 m). The complements of the and more preferably at least 99% identical to SEQ ID isolated nucleic acids are also encompassed by the present NO:291 except for containing one or more nucleotide vari invention. ants of Tables 34 and/or 35, or the complement thereof. 0410 Thus, for example, an isolated nucleic acid of the 0416) In another embodiment, the present invention pro present invention can have a contiguous span of at least 18, vides an isolated nucleic acid, naturally occurring or artifi 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 or 40 or 50 cial, having a nucleotide sequence encoding a AMFR pro nucleotide residues of SEQ ID NO:284 containing the tein having an amino acid sequence according to SEQ ID nucleotide variant EX1(a)-82m (nucleotide residue No. 51 NO:292 but containing one or more amino acid variants of in SEQID NO:284), or a contiguous span of at least 18, 19. Tables 34 and/or 35. Isolated nucleic acids having a nucle 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 or 40 or 50 otide sequence that is the complement of the sequence are nucleotide residues of SEQ ID NO:285 containing the also encompassed by the present invention. nucleotide variant EX6(a)91 m (nucleotide residue No. 51 in 0417. In addition, isolated nucleic acids are also provided SEQ ID NO:285), or the complements thereof. which have a nucleotide sequence encoding a protein having 0411 The present invention further provides an isolated an amino acid sequence that is at least 95%, preferably at AMFR nucleic acid containing at least one of the newly least 97% and more preferably at least 99% identical to SEQ discovered nucleotide variants as summarized in Tables 34 ID NO:292 but containing one or more amino acid variants and 35, or one or more nucleotide variants that will result in of Tables 34 and/or 35, or the complement thereof. the amino acid variants provided in Tables 34 and 35. The 0418. The present invention also encompasses an isolated term "AMFR nucleic acid' is as defined above and means a nucleic acid comprising the nucleotide sequence of a region naturally existing nucleic acid coding for a wild-type or of a AMFR genomic DNA or cDNA or mRNA, wherein the variant or mutant AMFR. The term “AMFR nucleic acid is region contains one or more nucleotide variants as provided inclusive and may be in the form of either double-stranded in Tables 34 and/or 35 above, or one or more nucleotide or single-stranded nucleic acids, and a single Strand can be variants that will give rise to one or more amino acid either of the two complementing strands. The isolated variants of Tables 34 and/or 35, or the complement thereof. AMFR nucleic acid can be naturally existing genomic DNA, Such regions can be isolated and analyzed to efficiently mRNA or cDNA. In one embodiment, the isolated AMFR detect the nucleotide variants of the present invention. Also, nucleic acid has a nucleotide sequence according to SEQID Such regions can also be isolated and used as probes or NO:291, but containing one or more exonic nucleotide primers in detection of the nucleotide variants of the present variants of Tables 34 and/or 35, or the complement thereof. invention and other uses as will be clear from the descrip In a specific embodiment, the isolated AMFR nucleic acid tions below. has a nucleotide sequence according to SEQID NO:291 but containing one or more exonic nucleotide variants of Hap 0419 Thus, in one embodiment, the isolated nucleic acid lotype I in Table 34, or the complement thereof. In another comprises a contiguous span of at least 12, 15, 17, 18, 19. specific embodiment, the isolated AMFR nucleic acid has a 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 50, 70 or 100 nucleotide sequence according to SEQ ID NO:291 except nucleotide residues of an AMFR nucleic acid, the contigu for containing one or more exonic nucleotide variants of ous span containing one or more nucleotide variants in Haplotype II in Table 35, or the complement thereof. Tables 34 and/or 35, or the complement thereof. In specific embodiments, the isolated nucleic acid are oligonucleotides 0412. In another embodiment, the isolated AMFR nucleic having a contiguous span of from about 17, 18, 19, 20, 21. acid has a nucleotide sequence that is at least 95%, prefer 22, 23 or 25 to about 30, 40 or 50, preferably from about 21 ably at least 97% and more preferably at least 99% identical to about 30 nucleotide residues, of any AMFR nucleic acid, to SEQ ID NO:291 but contains one or more exonic nucle said contiguous span containing one or more nucleotide otide variants of Table 1, or one or more nucleotide variants variants of Tables 34 and/or 35. that will result in one or more amino acid variants of Tables 34 and/or 35, or the complement thereof. 0420. In one embodiment, the isolated nucleic acid com prises a contiguous span of at least 12, 15, 17, 18, 19, 20, 21. 0413. In yet another embodiment, the isolated AMFR 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 50, 70 or 100 nucleic acid has a nucleotide sequence encoding AMFR nucleotide residues of any one of SEQ ID NOS:295-301, protein having an amino acid sequence according to SEQID containing one or more nucleotide variants Tables 34-35, or NO:292 but contains one or more amino acid variants of the complement thereof. In specific embodiments, the iso US 2007/0O82347 A1 Apr. 12, 2007 40 lated nucleic acid comprises a nucleotide sequence accord 0423) In the isolated TLK1, WARS2, ARTS2, MSR, ing to any one of SEQ ID NOS:295-301. In preferred AKAP9, DNAJD1, GOLPH4, RABEP1, TAP2, NARG2, embodiments, the isolated nucleic acid are oligonucleotides DDX58, CD39, FKBP1a, SRI, XRRA1, IRF5 or AMFR having a contiguous span of from about 17, 18, 19, 20, 21. oligonucleotides containing a nucleotide variant according 22, 23 or 25 to about 30, 40 or 50, preferably from about 21 to the present invention, the nucleotide variant can be to about 30 nucleotide residues, of any one of SEQ ID located in any position. In one embodiment, a nucleotide NOs:295-301 and containing one or more nucleotide vari variant is at the 5' or 3' end of the oligonucleotides. In a more ants of Table 1. The complements of the isolated nucleic preferred embodiment, a TLK1, WARS2, ARTS2, MSR, acids are also encompassed by the present invention. AKAP9, DNAJD1, GOLPH4, RABEP1, TAP2, NARG2, DDX58, CD39, FKBP1a, SRI, XRRA1, IRF5 or AMFR 0421. Thus, for example, an isolated nucleic acid of the oligonucleotide contains only one nucleotide variant accord present invention can have a contiguous span of at least 18, ing to the present invention, which is located at the 3' end of 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 or 40 or 50 the oligonucleotide. In another embodiment, a nucleotide nucleotide residues of SEQ ID NO:295 containing the variant of the present invention is located within no greater than four (4), preferably no greater than three (3), and more nucleotide variant EX4(a)+14C (nucleotide residue No. 51 in preferably no greater than two (2) nucleotides of the center SEQID NO:295), or a contiguous span of at least 18, 19, 20, of the oligonucleotide of the present invention. In more 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 or 40 or 50 nucleotide preferred embodiment, a nucleotide variant is located at the residues of SEQ ID NO:296 containing the nucleotide center or within one (1) nucleotide of the center of the variant EX12(a)+62G (nucleotide residue No. 51 in SEQ ID oligonucleotide. For purposes of defining the location of a NO:296), or a contiguous span of at least 18, 19, 20, 21, 22. nucleotide variant in an oligonucleotide, the center nucle 23, 24, 25, 26, 27, 28, 29, or 30 or 40 or 50 nucleotide otide of an oligonucleotide with an odd number of nucle residues of SEQ ID NO:297 containing the nucleotide otides is considered to be the center. For an oligonucleotide variant EX14(a)1359T (nucleotide residue No. 51 in SEQID with an even number of nucleotides, the bond between the NO:297), or a contiguous span of at least 18, 19, 20, 21, 22. two center nucleotides is considered to be the center. 23, 24, 25, 26, 27, 28, 29, or 30 or 40 or 50 nucleotide residues of SEQ ID NO:298 containing the nucleotide 0424. In other embodiments of the present invention, variant EX14(a)483A (nucleotide residue No. 51, in SEQID isolated nucleic acids are provided which encode a contigu NO:298), or the complements thereof. ous span of at least 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or 17 amino acids of an TLK1, WARS2, ARTS2, MSR, 0422. In preferred embodiments, an isolated oligonucle AKAP9, DNAJD1, GOLPH4, RABEP1, TAP2, NARG2, otide of the present invention is specific to a TLK1, WARS2, DDX58, CD39, FKBP1a, SRI, XRRA1, IRF5 or AMFR ARTS2, MSR, AKAP9, DNAJD1, GOLPH4, RABEP1, protein wherein said contiguous span contains at least one TAP2, NARG2, DDX58, CD39, FKBP1a, SRI, XRRA1, amino acid variant in Tables 1-35 according to the present IRF5 or AMFR allele (“allele-specific') containing one or invention. more nucleotide variants as disclosed in the present inven tion. That is, the isolated oligonucleotide is capable of 0425 The oligonucleotides of the present invention can selectively hybridizing, under high Stringency conditions have a detectable marker selected from, e.g., radioisotopes, generally recognized in the art, to a TLK1, WARS2, ARTS2, fluorescent compounds, enzymes, or enzyme co-factors MSR, AKAP9, DNAJD1, GOLPH4, RABEP1, TAP2, operably linked to the oligonucleotide. The oligonucleotides NARG2, DDX58, CD39, FKBP1a, SRI, XRRA1, IRF5 or of the present invention can be useful in genotyping as will AMFR genomic or cDNA or mRNA containing one or more be apparent from the description below. nucleotide variants as disclosed in the present invention, but 0426 In addition, the present invention also provides not to a TLK1, WARS2, ARTS2, MSR, AKAP9, DNAJD1, DNA microchips or microarray incorporating a variant GOLPH4, RABEP1, TAP2, NARG2, DDX58, CD39, TLK1, WARS2, ARTS2, MSR, AKAP9, DNAJD1, FKBP1a, SRI, XRRA1, IRF5 or AMFR gene. Such oligo GOLPH4, RABEP1, TAP2, NARG2, DDX58, CD39, nucleotides will be useful in a hybridization-based method FKBP1a, SRI, XRRA1, IRF5 or AMFR genomic DNA or for detecting the nucleotide variants of the present invention cDNA or mRNA or an oligonucleotide according to the as described in details below. An ordinarily skilled artisan present invention. The microchip will allow rapid genotyp would recognize various stringent conditions which enable ing and/or haplotyping in a large scale. the oligonucleotides of the present invention to differentiate between a TLK1, WARS2, ARTS2, MSR, AKAP9, 0427 AS is known in the art, in microchips, a large DNAJD1, GOLPH4, RABEP1, TAP2, NARG2, DDX58, number of different nucleic acid probes are attached or CD39, FKBP1a, SRI, XRRA1, IRF5 or AMFR gene having immobilized in an array on a solid Support, e.g., a silicon a reference sequence and a variant TLK1, WARS2, ARTS2, chip or glass slide. Target nucleic acid sequences to be MSR, AKAP9, DNAJD1, GOLPH4, RABEP1, TAP2, analyzed can be contacted with the immobilized oligonucle NARG2, DDX58, CD39, FKBP1a, SRI, XRRA1, IRF5 or otide probes on the microchip. See Lipshutz et al., Biotech AMFR gene of the present invention. For example, the niques, 19:442-447 (1995); Chee et al., Science, 274:610 hybridization can be conducted overnight in a solution 614 (1996); Kozal et al., Nat. Med. 2:753-759 (1996); Hacia containing 50% formamide, 5xSSC, pH7.6, 5x Denhardt's et al., Nat. Genet., 14:441-447 (1996); Saiki et al., Proc. solution, 10% dextran sulfate, and 20 microgram/ml dena Natl. Acad. Sci. USA, 86:6230-6234 (1989); Gingeras et al., tured, sheared salmon sperm DNA. The hybridization filters Genome Res., 8:435-448 (1998). The microchip technolo can be washed in 0.1 xSSC at about 65° C. Alternatively, gies combined with computerized analysis tools allow large typical PCR conditions employed in the art with an anneal scale high throughput Screening. See, e.g., U.S. Pat. No. ing temperature of about 55° C. can also be used. 5,925,525 to Fodor et al; Wilgenbus et al., J. Mol. Med., US 2007/0O82347 A1 Apr. 12, 2007

77:761-786 (1999); Graber et al., Curr. Opin. Biotechnol., ARTS1 peptides contain no greater than 200 or 100 amino 9:14-18 (1998); Hacia et al., Nat. Genet., 14:441-447 acids, and preferably no greater than 50 amino acids. In (1996); Shoemaker et al., Nat. Genet., 14:450-456 (1996): specific embodiments, the ARTS1 polypeptides in accor DeRisi et al., Nat. Genet., 14:457-460 (1996); Chee et al., dance with the present invention contain one or more of the Nat. Genet., 14:610-614 (1996); Lockhart et al., Nat. Genet., amino acid variants identified in accordance with the present 14:675-680 (1996); Drobyshev et al., Gene, 188:45-52 invention. The peptides can be useful in preparing antibodies (1997). specific to the mutant ARTS1 proteins provided in accor 0428. In a preferred embodiment, a DNA microchip is dance with the present invention. provided comprising a plurality of the oligonucleotides of 0432. Thus, as an example, an isolated polypeptide of the the present invention such that the nucleotide identity at present invention can have a contiguous span of at least 6, each of the nucleotide variant sites disclosed in Tables 1-35 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acid residues of SEQ can be determined in one single microarray. In a preferred ID NO:31 encompassing the amino acid variant P127R embodiment, the microchip incorporates a variant TLK1. (amino acid residue No. 127 in SEQ ID NO:31), or a WARS2, ARTS2, MSR, AKAP9, DNAJD1, GOLPH4, contiguous span of at least 6, 7, 8, 9, 10, 11, 12, 13, 14 or RABEP1, TAP2, NARG2, DDX58, CD39, FKBP1a, SRI, 15 amino acid residues of SEQID NO:31 encompassing the XRRA1, IRF5 or AMFR nucleic acid or oligonucleotide of amino acid variant Q725R (amino acid residue No. 725 in the present invention and contains at least two of the variants SEQ ID NO:31). in Tables 1-35 and 81, preferably at least ten, more prefer 0433. In another aspect, the present invention provides an ably at least 20, 30, 40, 50, or 100 of the variants in Table isolated MSR protein encoded by one of the novel MSR 1-35 and 81. gene variants according to the present invention. Thus, for 0429. In one embodiment, the DNA microchip is example, the present invention provides an isolated MSR designed to detect at least one nucleotide variant associated protein having an amino acid sequence according to SEQID with a high or low expression phenotype of at least two, NO:67 but containing one or more amino acid variants preferably at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or at selected from the group consisting of K350R or H595Y. In least 15 of the genes chosen from the group of TLK1, another example, the isolated MSR protein of the present WARS2, ARTS2, MSR, AKAP9, DNAJD1, RABEP1, invention has an amino acid sequence at least 95%, prefer TAP2, DDX58, FKBP1a, SRI, XRRA1, and AMFR. Pref ably 97%, more preferably 99% identical to SEQID NO:67 erably such a microchip is designed to detect at least one wherein the amino acid sequence contains at least one amino nucleotide variant associated with a high expression pheno acid variant selected from the group consisting of K350R or type and at least one nucleotide variant associated with a low H595Y. expression phenotype of at least two, preferably at least 3, 4, 0434. In addition, the present invention also encompasses 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or at least 15 of the genes isolated peptides having a contiguous span of at least 6, 7, chosen from the group of TLK1, WARS2, ARTS2, MSR, 8, 9, 10, 11, 12, 13, 15, 17, 19 or 21 or more amino acids of AKAP9, DNAJD1, RABEP1, TAP2, DDX58, FKBP1a, an isolated MSR protein of the present invention said SRI, XRRA1, and AMFR. Such microchips can be used in contiguous span encompassing one or more amino acid diagnostic or prognostic or pharmacogenetic response variants selected from the group consisting of K350R or assays related to cancer. Such variants are according to the H595Y. In preferred embodiments, the isolated variant MSR present invention selected from those in Tables 1-35 and 81. peptides contain no greater than 200 or 100 amino acids, and The variants can be contained in nucleic acids, particularly preferably no greater than 50 amino acids. In specific oligonucleotides in the DNA microchip. embodiments, the MSR polypeptides in accordance with the present invention contain one or more of the amino acid 4. Proteins and Peptides variants identified in accordance with the present invention. 0430. In one aspect, the present invention provides an The peptides can be useful in preparing antibodies specific isolated ARTS1 protein encoded by one of the novel ARTS1 to the mutant MSR proteins provided in accordance with the gene variants according to the present invention. Thus, for present invention. example, the present invention provides an isolated ARTS1 0435 Thus, as an example, an isolated polypeptide of the protein having an amino acid sequence according to SEQID present invention can have a contiguous span of at least 6, NO:31 but containing one or more amino acid variants 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acid residues of SEQ selected from the group consisting of P127R and Q725R. In ID NO:67 encompassing the amino acid variant H595Y another example, the isolated ARTS1 protein of the present (amino acid residue No. 595 in SEQID NO:67), or encom invention has an amino acid sequence at least 95%, prefer passing the amino acid variant K350R (amino acid residue ably 97%, more preferably 99% identical to SEQID NO:31 No. 350 in SEQ ID NO:67). wherein the amino acid sequence contains at least one amino 0436 The present invention also provides isolated pro acid variant selected from the group consisting of P127R teins encoded by one of the isolated nucleic acids according and Q725R. to the present invention. In one aspect, the present invention 0431. In addition, the present invention also encompasses provides an isolated AKAP9 protein encoded by one of the isolated peptides having a contiguous span of at least 6, 7, novel AKAP9 gene variants according to the present inven 8, 9, 10, 11, 12, 13, 15, 17, 19 or 21 or more amino acids of tion. Thus, for example, the present invention provides an an isolated ARTS1 protein of the present invention said isolated AKAP9 protein having an amino acid sequence contiguous span encompassing one or more amino acid according to SEQ ID NO:91 but containing one or more variants selected from the group consisting of P127R and amino acid variants selected from the group consisting of Q725R. In preferred embodiments, the isolated variant N2792S and M463I. In another example, the isolated US 2007/0O82347 A1 Apr. 12, 2007 42

AKAP9 protein of the present invention has an amino acid TAP2 gene variants according to the present invention. sequence at least 95%, preferably 97%, more preferably Thus, for example, the present invention provides an iso 99% identical to SEQ ID NO:91 wherein the amino acid lated TAP2 protein having an amino acid sequence accord sequence contains at least one amino acid variant selected ing to SEQ ID NO:203 but containing one or more amino from the group consisting of N2792S and M463I. acid variants selected from the group consisting of A665T and R651C. In another example, the isolated TAP2 protein 0437. In addition, the present invention also encompasses of the present invention has an amino acid sequence at least isolated peptides having a contiguous span of at least 6, 7, 95%, preferably 97%, more preferably 99% identical to SEQ 8, 9, 10, 11, 12, 13, 15, 17, 19 or 21 or more amino acids of an isolated AKAP9 protein of the present invention said ID NO:203 wherein the amino acid sequence contains at contiguous span encompassing one or more amino acid least one amino acid variant selected from the group con variants selected from the group consisting of N2792S and sisting of R651C and A665T. M463I. In preferred embodiments, the isolated variant 0443). In addition, the present invention also encompasses AKAP9 peptides contain no greater than 200 or 100 amino isolated peptides having a contiguous span of at least 6, 7, acids, and preferably no greater than 50 amino acids. In 8, 9, 10, 11, 12, 13, 15, 17, 19 or 21 or more amino acids of specific embodiments, the AKAP9 polypeptides in accor an isolated TAP2 protein of the present invention said dance with the present invention contain one or more of the contiguous span encompassing one or more amino acid amino acid variants identified in accordance with the present variants selected from the group consisting of R651C and invention. The peptides can be useful in preparing antibodies A665T. In preferred embodiments, the isolated variant TAP2 specific to the mutant AKAP9 proteins provided in accor peptides contain no greater than 200 or 100 amino acids, and dance with the present invention. preferably no greater than 50 amino acids. In specific 0438 Thus, as an example, an isolated polypeptide of the embodiments, the TAP2 polypeptides in accordance with the present invention can have a contiguous span of at least 6, present invention contain one or more of the amino acid 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acid residues of SEQ variants identified in accordance with the present invention. ID NO:91 encompassing the amino acid variant M463I The peptides can be useful in preparing antibodies specific (amino acid residue No. 463 in SEQ ID NO:91), or a to the mutant TAP2 proteins provided in accordance with the contiguous span of at least 6, 7, 8, 9, 10, 11, 12, 13, 14 or present invention. 15 amino acid residues of SEQID NO:91 encompassing the 0444 Thus, as an example, an isolated polypeptide of the amino acid variant N2792S (amino acid residue No. 2792 in present invention can have a contiguous span of at least 6, SEQ ID NO:91). 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acid residues of SEQ 0439. In another aspect, the present invention provides an ID NO:203 encompassing the amino acid variant R651C isolated DNAJD1 protein encoded by one of the novel (amino acid residue No. 651 in SEQ ID NO:203), or a DNAJD1 gene variants according to the present invention. contiguous span of at least 6, 7, 8, 9, 10, 11, 12, 13, 14 or Thus, for example, the present invention provides an iso 15 amino acid residues of SEQ ID NO:203 encompassing lated DNAJD1 protein having an amino acid sequence the amino acid variant A665T (amino acid residue No. 665 according to SEQID NO:150 but containing the amino acid in SEQ ID NO:195). variant R35G. In another example, the isolated DNAJD1 0445. The present invention also provides isolated pro protein of the present invention has an amino acid sequence teins encoded by one of the isolated nucleic acids according at least 95%, preferably 97%, more preferably 99% identical to the present invention. In one aspect, the present invention to SEQ ID NO:150 wherein the amino acid sequence provides an isolated XRRA1 protein encoded by one of the contains the amino acid variant R35G. novel XRRA1 gene variants according to the present inven 0440. In addition, the present invention also encompasses tion. Thus, for example, the present invention provides an isolated peptides having a contiguous span of at least 6, 7, isolated XRRA1 protein having an amino acid sequence 8, 9, 10, 11, 12, 13, 15, 17, 19 or 21 or more amino acids of according to SEQ ID NO:258 but containing one or more an isolated DNAJD1 protein of the present invention said amino acid variants selected from the group consisting of contiguous span encompassing the amino acid variant P38R and T502R. In another example, the isolated XRRA1 R35G. In preferred embodiments, the isolated variant protein of the present invention has an amino acid sequence DNAJD1 peptides contain no greater than 200 or 100 amino at least 95%, preferably 97%, more preferably 99% identical acids, and preferably no greater than 50 amino acids. In to SEQ ID NO:258 wherein the amino acid sequence specific embodiments, the DNAJD1 polypeptides in accor contains at least one amino acid variant selected from the dance with the present invention contain the amino acid group consisting of P38R and T502R. variant identified in accordance with the present invention. 0446. In addition, the present invention also encompasses The peptides can be useful in preparing antibodies specific isolated peptides having a contiguous span of at least 6, 7, to the mutant DNAJD1 proteins provided in accordance with 8, 9, 10, 11, 12, 13, 15, 17, 19 or 21 or more amino acids of the present invention. an isolated XRRA1 protein of the present invention said 0441 Thus, as an example, an isolated polypeptide of the contiguous span encompassing one or more amino acid present invention can have a contiguous span of at least 6, variants selected from the group consisting of P38R and T502R. In preferred embodiments, the isolated variant 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acid residues of SEQ XRRA1 peptides contain no greater than 200 or 100 amino ID NO:150 encompassing the amino acid variant R35G acids, and preferably no greater than 50 amino acids. In (amino acid residue No. 35 in SEQ ID NO:150). specific embodiments, the XRRA1 polypeptides in accor 0442. In yet another aspect, the present invention pro dance with the present invention contain one or more of the vides an isolated TAP2 protein encoded by one of the novel amino acid variants identified in accordance with the present US 2007/0O82347 A1 Apr. 12, 2007 invention. The peptides can be useful in preparing antibodies state, i.e., as self-replicating plasmids or viruses. Alterna specific to the mutant XRRA1 proteins provided in accor tively, the vector construct can be integrated into chromo dance with the present invention. Somes of the host cells by conventional techniques such as 0447 Thus, as an example, an isolated polypeptide of the selection of stable cell lines or site-specific recombination. present invention can have a contiguous span of at least 6, The vector construct can be designed to be suitable for 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acid residues of SEQ expression in various host cells, including but not limited to ID NO:258 encompassing the amino acid variant P38R bacteria, yeast cells, plant cells, insect cells, and mammalian (amino acid residue No. 38 in SEQ ID NO:258), or a and human cells. A skilled artisan will recognize that the contiguous span of at least 6, 7, 8, 9, 10, 11, 12, 13, 14 or designs of the vectors can vary with the host cell used. 15 amino acid residues of SEQ ID NO:258 encompassing the amino acid variant T502R (amino acid residue No. 502 5. Antibodies in SEQ ID NO:258). 0450. The present invention also provides antibodies 0448. As will be apparent to an ordinarily skilled artisan, selectively immunoreactive with a variant ARTS2, MSR, the isolated nucleic acids and isolated polypeptides of the AKAP9, DNAJD1, TAP2, or XRRA1 protein or peptide present invention can be prepared using techniques gener provided in accordance with the present invention and ally known in the field of molecular biology. See generally, methods for making the antibodies. As used herein, the term Sambrook et al., Molecular Cloning. A Laboratory Manual, 'antibody encompasses both monoclonal and polyclonal 2" ed., Cold Spring Harbor Laboratory, Cold Spring Harbor, antibodies that fall within any antibody classes, e.g., IgG, N.Y., 1989. The isolated ARTS2, MSR, AKAP9, DNAJD1, IgM, IgA, etc. The term “antibody' also means antibody TAP2, or XRRA1 gene or cDNA or oligonucleotides of this fragments including, but not limited to, Fab and F(ab'), invention can be operably linked to one or more other DNA conjugates of Such fragments, and single-chain antibodies fragments. For example, the isolated ARTS2, MSR, AKAP9, that can be made in accordance with U.S. Pat. No. 4,704, DNAJD1, TAP2, or XRRA1 nucleic acid (e.g., cDNA or 692, which is incorporated herein by reference. Specifically, oligonucleotides) can be ligated to another DNA such that a the phrase “selectively immunoreactive with one or more of fusion protein can be encoded by the ligation product. The the newly discovered variant ARTS2, MSR, AKAP9, DNAJD1, TAP2, or XRRA1 protein variants” as used herein isolated ARTS2, MSR, AKAP9, DNAJD1, TAP2, or means that the immunoreactivity of an antibody with a XRRA1 nucleic acid (e.g., cDNA or oligonucleotides) can protein variant of the present invention is substantially also be incorporated into a DNA vector for purposes of, e.g., higher than that with the ARTS2, MSR, AKAP9, DNAJD1, amplifying the nucleic acid or a portion thereof, and/or TAP2, or XRRA1 protein heretofore known in the art such expressing a mutant ARTS2, MSR, AKAP9, DNAJD1, that the binding of the antibody to the protein variant of the TAP2, or XRRA1 polypeptide or a fusion protein thereof. present invention is readily distinguishable, based on the 0449 Thus, the present invention also provides a vector strength of the binding affinities, from the binding of the construct containing an isolated nucleic acid of the present antibody to the ARTS2, MSR, AKAP9, DNAJD1, TAP2, or invention, such as a mutant ARTS2, MSR, AKAP9, XRRA1 protein having a reference amino acid sequence. DNAJD1, TAP2, or XRRA1 nucleic acid (e.g., cDNA or Preferably, the binding constant differs by a magnitude of at oligonucleotides) of the present invention. Generally, the least 2 fold, more preferably at least 5 fold, even more vector construct may include a promoter operably linked to preferably at least 10 fold, and most preferably at least 100 a DNA of interest (including a full-length sequence or a fold. fragment thereof in the 5' to 3’ direction or in the reverse direction for purposes of producing antisense nucleic acids), 0451. To make such an antibody, a variant ARTS2, MSR, an origin of DNA replication for the replication of the vector AKAP9, DNAJD1, TAP2, or XRRA1 protein or a peptide of in host cells and a replication origin for the amplification of the present invention having a particular amino acid variant the vector in, e.g., E. coli, and selection marker(s) for (e.g., Substitution or insertion or deletion) is provided and selecting and maintaining only those host cells harboring the used to immunize an animal. The variant ARTS2, MSR, vector. Additionally, the vector preferably also contains AKAP9, DNAJD1, TAP2, or XRRA1 protein or peptide inducible elements, which function to control the expression variant can be made by any methods known in the art, e.g., of the isolated gene sequence. Other regulatory sequences by recombinant expression or chemical synthesis. To Such as transcriptional termination sequences and translation increase the specificity of the antibody, a shorter peptide regulation sequences (e.g., Shine-Dalgarno sequence) can containing an amino acid variant is preferably generated and also be included. An epitope tag-coding sequence for detec used as antigen. Techniques for immunizing animals for the tion and/or purification of the encoded polypeptide can also purpose of making polyclonal antibodies are generally be incorporated into the vector construct. Examples of known in the art. See Harlow and Lane, Antibodies. A useful epitope tags include, but are not limited to, influenza Laboratory Manual, Cold Spring Harbor Laboratory, Cold virus hemagglutinin (HA), Simian Virus 5 (V5), polyhisti Spring Harbor, N.Y., 1988. A carrier may be necessary to dine (6xHis), c-myc, lacZ. GST, and the like. Proteins with increase the immunogenicity of the polypeptide. Suitable polyhistidine tags can be easily detected and/or purified with carriers known in the art include, but are not limited to, Ni affinity columns, while specific antibodies to many liposome, macromolecular protein or polysaccharide, or epitope tags are generally commercially available. The vec combination thereof. Preferably, the carrier has a molecular tor construct can be introduced into the host cells or organ weight in the range of about 10,000 to 1,000,000. The isms by any techniques known in the art, e.g., by direct DNA polypeptide may also be administered along with an adju transformation, microinjection, electroporation, Viral infec vant, e.g., complete Freund's adjuvant. tion, lipofection, gene gun, and the like. The vector construct 0452. The antibodies of the present invention preferably can be maintained in host cells in an extrachromosomal are monoclonal. Such monoclonal antibodies may be devel US 2007/0O82347 A1 Apr. 12, 2007 44 oped using any conventional techniques known in the art. lication No. WO 94/02602; Green et. al., Nat. Genetics, 7: For example, the popular hybridoma method disclosed in 13-21 (1994); and Lonberg et al., Nature 368: 856-859 Kohler and Milstein, Nature, 256:495-497 (1975) is now a (1994), all of which are incorporated herein by reference. well-developed technique that can be used in the present The transgenic non-human host animal may be immunized invention. See U.S. Pat. No. 4,376,110, which is incorpo with Suitable antigens such as a protein variant of the present rated herein by reference. Essentially, B-lymphocytes pro invention to illicit a specific immune response thus produc ducing a polyclonal antibody against a protein variant of the ing humanized antibodies. In addition, cell lines producing present invention can be fused with myeloma cells to specific humanized antibodies can also be derived from the generate a library of hybridoma clones. The hybridoma immunized transgenic non-human animals. For example, population is then screened for antigen binding specificity mature B-lymphocytes obtained from a transgenic animal and also for immunoglobulin class (isotype). In this manner, producing humanized antibodies can be fused to myeloma pure hybridoma clones producing specific homogenous anti cells and the resulting hybridoma clones may be selected for bodies can be selected. See generally, Harlow and Lane, specific humanized antibodies with desired binding speci Antibodies: A Laboratory Manual, Cold Spring Harbor ficities. Alternatively, cDNAs may be extracted from mature Press, 1988. Alternatively, other techniques known in the art B-lymphocytes and used in establishing a library which is may also be used to prepare monoclonal antibodies, which Subsequently screened for clones encoding humanized anti include but are not limited to the EBV hybridoma technique, bodies with desired binding specificities. the human N-cell hybridoma technique, and the trioma technique. 0455. In a specific embodiment, the antibody is selec tively immunoreactive with a variant ARTS1 protein or 0453. In addition, antibodies selectively immunoreactive peptide containing the amino acid variant P127R and/or with a protein or peptide variant of the present invention Q725R. may also be recombinantly produced. For example, cDNAs prepared by PCR amplification from activated B-lympho 0456. In another specific embodiment, the antibody is cytes or hybridomas may be cloned into an expression selectively immunoreactive with a variant MSR protein or vector to form a cDNA library, which is then introduced into peptide containing the amino acid variant K350R and/or a host cell for recombinant expression. The cDNA encoding H595Y. a specific protein may then be isolated from the library. The 0457. In another specific embodiment, the antibody is isolated cDNA can be introduced into a suitable host cell for selectively immunoreactive with a variant AKAP9 protein or the expression of the protein. Thus, recombinant techniques peptide containing the amino acid variant N2792S and/or can be used to recombinantly produce specific native anti M463I. bodies, hybrid antibodies capable of simultaneous reaction with more than one antigen, chimeric antibodies (e.g., the 0458 In another specific embodiment, the antibody is constant and variable regions are derived from different selectively immunoreactive with a variant DNAJD1 protein Sources), univalent antibodies which comprise one heavy or peptide containing the amino acid variant R35G. and light chain pair coupled with the Fc region of a third 0459. In yet another specific embodiment, the antibody is (heavy) chain, Fab proteins, and the like. See U.S. Pat. No. selectively immunoreactive with a variant TAP2 protein or 4,816,567; European Patent Publication No. 0088994: peptide containing the amino acid variant R651C and/or Munro, Nature, 312:597 (1984); Morrison, Science, T665A. 229:1202 (1985); Oi et al., BioTechniques, 4:214 (1986); and Wood et al., Nature, 314:446-449 (1985), all of which 0460. In yet another specific embodiment, the antibody is are incorporated herein by reference. Antibody fragments selectively immunoreactive with a variant XRRA1 protein Such as Fv fragments, single-chain Fv fragments (scEv), Fab' or peptide containing the amino acid variant P38R and/or fragments, and F(ab')2 fragments can also be recombinantly T5O2R. produced by methods disclosed in, e.g., U.S. Pat. No. 4,946,778; Skerra & Plickthun, Science, 240:1038-1041 6. Genotyping (1988); Better et al., Science, 240:1041-1043 (1988); and Bird, et al., Science, 242:423-426 (1988), all of which are 0461 The present invention provides methods for geno incorporated herein by reference. typing the TLK1, WARS2, ARTS2, MSR, AKAP9, 0454. In a preferred embodiment, the antibodies provided DNAJD1, GOLPH4, RABEP1, TAP2, NARG2, DDX58, in accordance with the present invention are partially or CD39, FKBP1a, SRI, XRRA1, IRF5 and AMFR genes by fully humanized antibodies. For this purpose, any methods determining whether an individual, or a tissue sample from known in the art may be used. For example, partially an individual, has a nucleotide variant or amino acid variant humanized chimeric antibodies having V regions derived of the present invention. from the tumor-specific mouse monoclonal antibody, but 0462 Similarly, methods for haplotyping the TLK1, human C regions are disclosed in Morrison and Oi, Adv. WARS2, ARTS2, MSR, AKAP9, DNAJD1, GOLPH4, Immunol., 44:65-92 (1989). In addition, fully humanized RABEP1, TAP2, NARG2, DDX58, CD39, FKBP1a, SRI, antibodies can be made using transgenic non-human ani XRRA1, IRF5 and AMFR genes are also provided. Haplo mals. For example, transgenic non-human animals such as typing can be done by any methods known in the art. For transgenic mice can be produced in which endogenous example, only one copy of the TLK1, WARS2, ARTS2, immunoglobulin genes are suppressed or deleted, while MSR, AKAP9, DNAJD1, GOLPH4, RABEP1, TAP2, heterologous antibodies are encoded entirely by exogenous NARG2, DDX58, CD39, FKBP1a, SRI, XRRA1, IRF5 or immunoglobulin genes, preferably human immunoglobulin AMFR gene can be isolated from an individual, or from a genes, recombinantly introduced into the genome. See e.g., tissue sample from an individual, and the nucleotide at each U.S. Pat. Nos. 5,530,101: 5,545,806; 6,075,181; PCT Pub of the variant positions is determined. Alternatively, an allele US 2007/0O82347 A1 Apr. 12, 2007

specific PCR or a similar method can be used to amplify other lymphocytes have cell nuclei, while red blood cells are only one copy of the TLK1, WARS2, ARTS2, MSR, anucleate and contain only mRNA. Nevertheless, mRNA is AKAP9, DNAJD1, GOLPH4, RABEP1, TAP2, NARG2, also useful as it can be analyzed for the presence of DDX58, CD39, FKBP1a, SRI, XRRA1, IRF5 or AMFR nucleotide variants in its sequence or serve as template for gene in an individual, or the tissue sample, and the SNPs at cDNA synthesis. The tissue or cell samples, whether from the variant positions of the present invention are determined. the Somatic tissues of an individual, or from a biopsy of a The Clark method known in the art can also be employed for cancerous growth or tumor, can be analyzed directly without haplotyping. A high throughput molecular haplotyping much processing. Alternatively, nucleic acids including the method is also disclosed in Tost et al., Nucleic Acids Res., target sequence can be extracted, purified, and/or amplified 30(19):e96 (2002), which is incorporated herein by refer before they are subject to the various detecting procedures CCC. discussed below. Other than tissue or cell samples, cDNAs or genomic DNAs from a cDNA or genomic DNA library 0463 Thus, additional variant(s) that are in linkage dis constructed using a tissue or cell sample obtained from the equilibrium with the variants and/or haplotypes of the individual to be tested, or from a biopsy of a cancerous present invention can be identified by a haplotyping method growth or tumor from an individual, are also useful. known in the art, as will be apparent to a skilled artisan in the field of genetics and haplotying. The additional variants 0467 To determine the presence or absence of a particu that are in linkage disequilibrium with a variant or haplotype lar nucleotide variant, one technique is simply sequencing of the present invention can also be useful in the various the target genomic DNA or cDNA, particularly the region applications as described below. encompassing the nucleotide variant locus to be detected. Various sequencing techniques are generally known and 0464 For purposes of genotyping and haplotyping, both widely used in the art including the Sanger method and genomic DNA and mRNA/cDNA can be used, and both are Gilbert chemical method. The newly developed pyrose herein referred to generically as “gene.” quencing method monitors DNA synthesis in real time using 0465 Numerous techniques for detecting nucleotide vari a luminometric detection system. Pyrosequencing has been ants are known in the art and can all be used for the method shown to be effective in analyzing genetic polymorphisms of this invention. The techniques can be protein-based or Such as single-nucleotide polymorphisms and thus can also DNA-based. In either case, the techniques used must be be used in the present invention. See Nordstrom et al., Sufficiently sensitive so as to accurately detect the Small Biotechnol. Appl. Biochem., 31(2):107-112 (2000); Ahma nucleotide or amino acid variations. Very often, a probe is dian et al., Anal. Biochem., 280:103-110 (2000). utilized which is labeled with a detectable marker. Unless 0468 Alternatively, the restriction fragment length poly otherwise specified in a particular technique described morphism (RFLP) and AFLP method may also prove to be below, any Suitable marker known in the art can be used, useful techniques. In particular, if a nucleotide variant in the including but not limited to, radioactive isotopes, fluorescent target TLK1, WARS2, ARTS2, MSR, AKAP9, DNAJD1, compounds, biotin which is detectable using Strepavidin, GOLPH4, RABEP1, TAP2, NARG2, DDX58, CD39, enzymes (e.g., alkaline phosphatase), Substrates of an FKBP1a, SRI, XRRA1, IRF5 or AMFR DNA results in the enzyme, ligands and antibodies, etc. See Jablonski et al., elimination or creation of a restriction enzyme recognition Nucleic Acids Res., 14:6115-6128 (1986): Nguyen et al., site, then digestion of the target DNA with that particular Biotechniques, 13:116-123 (1992); Rigby et al., J. Mol. restriction enzyme will generate an altered restriction frag Biol., 113:237-251 (1977). ment length pattern. Thus, a detected RFLP or AFLP will 0466 In a DNA-based detection method, a target DNA indicate the presence of a particular nucleotide variant. sample, i.e., a sample containing TLK1, WARS2, ARTS2, 0469 Another useful approach is the single-stranded MSR, AKAP9, DNAJD1, GOLPH4, RABEP1, TAP2, conformation polymorphism assay (SSCA), which is based NARG2, DDX58, CD39, FKBP1a, SRI, XRRA1, IRF5 or on the altered mobility of a single-stranded target DNA AMFR genomic DNA or cDNA or mRNA must be obtained spanning the nucleotide variant of interest. A single nucle from the individual to be tested, or from a tissue sample from otide change in the target sequence can result in different the individual to be tested. Any tissue or cell sample intramolecular base pairing pattern, and thus different sec containing the TLK1, WARS2, ARTS2, MSR, AKAP9, ondary structure of the single-stranded DNA, which can be DNAJD1, GOLPH4, RABEP1, TAP2, NARG2, DDX58, detected in a non-denaturing gel. See Orita et al., Proc. Natl. CD39, FKBP1a, SRI, XRRA1, IRF5 or AMFR genomic Acad. Sci. USA, 86:2776-2770 (1989). Denaturing gel-based DNA, mRNA, or cDNA or a portion thereof can be used. techniques such as clamped denaturing gel electrophoresis However, in situations where the individual to be tested is (CDGE) and denaturing gradient gel electrophoresis thought or known to have cancer, a tissue sample may (DGGE) detect differences in migration rates of mutant preferentially be obtained from the cancerous growth or sequences as compared to wild-type sequences in denaturing tumor by biopsy. In Such situations, it may be important to gel. See Miller et al., Biotechniques, 5:1016-24 (1999); ensure that the biopsy sample is primarily composed of Sheffield et al., Am. J. Hum, Genet., 49:699-706 (1991); cancerous cells, since it may be advantageous to specifically Wartellet al., Nucleic Acids Res., 18:2699-2705 (1990); and genotype the cancerous growth or tumor, instead of, or in Sheffield et al., Proc. Natl. Acad. Sci. USA, 86:232-236 addition to, the Somatic tissues of the individual being (1989). In addition, the double-strand conformation analysis tested. For all genotyping methods, a tissue sample contain (DSCA) can also be useful in the present invention. See ing cell nucleus and thus genomic DNA can be obtained Arguello et al., Nat. Genet., 18:192-194 (1998). from the individual or from the cancerous growth or tumor within the individual. For genotyping somatic tissues, blood 0470 The presence or absence of a nucleotide variant at samples can be useful, except that only white blood cells and a particular locus in the TLK1, WARS2, ARTS2, MSR, US 2007/0O82347 A1 Apr. 12, 2007 46

AKAP9, DNAJD1, GOLPH4, RABEP1, TAP2, NARG2, IRF5 or AMFR gene, the other having a nucleotide sequence DDX58, CD39, FKBP1a, SRI, XRRA1, IRF5 or AMFR matching the TLK1, WARS2, ARTS2, MSR, AKAP9, gene of an individual can also be detected using the ampli DNAJD1, GOLPH4, RABEP1, TAP2, NARG2, DDX58, fication refractory mutation system (ARMS) technique. See CD39, FKBP1a, SRI, XRRA1, IRF5 or AMFR sequence e.g., European Patent No. 0.332.435; Newton et al., Nucleic immediately 3' downstream from the locus in the TLK1, Acids Res., 17:2503-2515 (1989); Fox et al., Br. J. Cancer WARS2, ARTS2, MSR, AKAP9, DNAJD1, GOLPH4, 77:1267-1274 (1998); Robertson et al., Eur: Respir: J, RABEP1, TAP2, NARG2, DDX58, CD39, FKBP1a, SRI, 12:477-482 (1998). In the ARMS method, a primer is XRRA1, IRF5 or AMFR gene. The oligonucleotides can be synthesized matching the nucleotide sequence immediately labeled for the purpose of detection. Upon hybridizing to the 5' upstream from the locus being tested except that the 3'-end target TLK1, WARS2, ARTS2, MSR, AKAP9, DNAJD1, nucleotide which corresponds to the nucleotide at the locus GOLPH4, RABEP1, TAP2, NARG2, DDX58, CD39, is a predetermined nucleotide. For example, the 3'-end FKBP1a, SRI, XRRA1, IRF5 or AMFR gene under a nucleotide can be the same as that in the mutated locus. The stringent condition, the two oligonucleotides are Subject to primer can be of any Suitable length so long as it hybridizes ligation in the presence of a suitable ligase. The ligation of to the target DNA under stringent conditions only when its the two oligonucleotides would indicate that the target DNA 3'-end nucleotide matches the nucleotide at the locus being has a nucleotide variant at the locus being detected. tested. Preferably the primer has at least 12 nucleotides, 0473 Detection of small genetic variations can also be more preferably from about 18 to 50 nucleotides. If the accomplished by a variety of hybridization-based individual tested has a mutation at the locus and the nucle approaches. Allele-specific oligonucleotides are most useful. otide therein matches the 3'-end nucleotide of the primer, See Conner et al., Proc. Natl. Acad. Sci. USA, 80:278-282 then the primer can be further extended upon hybridizing to (1983); Saiki et al. Proc. Natl. Acad. Sci. USA, 86:6230 the target DNA template, and the primer can initiate a PCR 6234 (1989). Oligonucleotide probes (allele-specific) amplification reaction in conjunction with another Suitable hybridizing specifically to a TLK1, WARS2, ARTS2, MSR, PCR primer. In contrast, if the nucleotide at the locus is of AKAP9, DNAJD1, GOLPH4, RABEP1, TAP2, NARG2, wild type, then primer extension cannot be achieved. Vari DDX58, CD39, FKBP1a, SRI, XRRA1, IRF5 or AMFR ous forms of ARMS techniques developed in the past few gene allele having a particular gene variant at a particular years can be used. See e.g., Gibson et al., Clin. Chem. locus but not to other alleles can be designed by methods 43:1336-1341 (1997). known in the art. The probes can have a length of e.g., from 0471 Similar to the ARMS technique is the mini 10 to about 50 nucleotide bases. The target TLK1, WARS2, sequencing or single nucleotide primer extension method, ARTS2, MSR, AKAP9, DNAJD1, GOLPH4, RABEP1, which is based on the incorporation of a single nucleotide. TAP2, NARG2, DDX58, CD39, FKBP1a, SRI, XRRA1, An oligonucleotide primer matching the nucleotide IRF5 or AMFR DNA and the oligonucleotide probe can be sequence immediately 5' to the locus being tested is hybrid contacted with each other under conditions sufficiently strin ized to the target DNA or mRNA in the presence of labeled gent such that the nucleotide variant can be distinguished dideoxyribonucleotides. A labeled nucleotide is incorpo from the wild-type TLK1, WARS2, ARTS2, MSR, AKAP9, rated or linked to the primer only when the dideoxyribo DNAJD1, GOLPH4, RABEP1, TAP2, NARG2, DDX58, nucleotides matches the nucleotide at the variant locus being CD39, FKBP1a, SRI, XRRA1, IRF5 or AMFR gene based detected. Thus, the identity of the nucleotide at the variant on the presence or absence of hybridization. The probe can locus can be revealed based on the detection label attached be labeled to provide detection signals. Alternatively, the to the incorporated dideoxyribonucleotides. See Syvanen et allele-specific oligonucleotide probe can be used as a PCR al., Genomics, 8:684-692 (1990); Shumaker et al., Hum. amplification primer in an “allele-specific PCR and the Mutat., 7:346-354 (1996); Chen et al., Genome Res., 10:549 presence or absence of a PCR product of the expected length 547 (2000). would indicate the presence or absence of a particular 0472. Another set of techniques useful in the present nucleotide variant. invention is the so-called "oligonucleotide ligation assay” 0474. Other useful hybridization-based techniques allow (OLA) in which differentiation between a wild-type locus two single-stranded nucleic acids annealed together even in and a mutation is based on the ability of two oligonucle the presence of mismatch due to nucleotide Substitution, otides to anneal adjacent to each other on the target DNA insertion or deletion. The mismatch can then be detected molecule allowing the two oligonucleotides joined together using various techniques. For example, the annealed by a DNA ligase. See Landergren et al., Science, 241:1077 duplexes can be subject to electrophoresis. The mismatched 1080 (1988); Chen et al, Genome Res., 8:549-556 (1998); duplexes can be detected based on their electrophoretic Iannone et al., Cytometry, 39:131-140 (2000). Thus, for mobility that is different from the perfectly matched example, to detect a single-nucleotide mutation at a particu duplexes. See Cariello, Human Genetics, 42:726 (1988). lar locus in the TLK1, WARS2, ARTS2, MSR, AKAP9, Alternatively, in a RNase protection assay, a RNA probe can DNAJD1, GOLPH4, RABEP1, TAP2, NARG2, DDX58, be prepared spanning the nucleotide variant site to be CD39, FKBP1a, SRI, XRRA1, IRF5 or AMFR gene, two detected and having a detection marker. See Giunta et al., oligonucleotides can be synthesized, one having the TLK1. Diagn. Mol. Path., 5:265-270 (1996): Finkelstein et al., WARS2, ARTS2, MSR, AKAP9, DNAJD1, GOLPH4, Genomics, 7:167-172 (1990); Kinszler et al., Science RABEP1, TAP2, NARG2, DDX58, CD39, FKBP1a, SRI, 251:1366-1370 (1991). The RNA probe can be hybridized to XRRA1, IRF5 or AMFR sequence just 5' upstream from the the target DNA or mRNA forming a heteroduplex that is locus with its 3' end nucleotide being identical to the then subject to the ribonuclease RNase A digestion. RNase nucleotide in the variant locus of the TLK1, WARS2, A digests the RNA probe in the heteroduplex only at the site ARTS2, MSR, AKAP9, DNAJD1, GOLPH4, RABEP1, of mismatch. The digestion can be determined on a dena TAP2, NARG2, DDX58, CD39, FKBP1a, SRI, XRRA1, turing electrophoresis gel based on size variations. In addi US 2007/0O82347 A1 Apr. 12, 2007 47 tion, mismatches can also be detected by chemical cleavage WARS2, ARTS2, MSR, AKAP9, DNAJD1, GOLPH4, methods known in the art. See e.g., Roberts et al., Nucleic RABEP1, TAP2, NARG2, DDX58, CD39, FKBP1a, SRI, Acids Res., 25:3377-3378 (1997). XRRA1, IRF5 or AMFR DNA template, the 5'-end of the 0475. In the mutS assay, a probe can be prepared match Taq Man probe will be degraded by Taq polymerase during ing the TLK1, WARS2, ARTS2, MSR, AKAP9, DNAJD1, the PCR reaction thus separating the reporting fluorophore GOLPH4, RABEP1, TAP2, NARG2, DDX58, CD39, from the quenching fluorophore and releasing fluorescence FKBP1a, SRI, XRRA1, IRF5 or AMFR gene sequence signals. See Holland et al., Proc. Natl. Acad. Sci. USA, Surrounding the locus at which the presence or absence of a 88:7276-7280 (1991); Kalinina et al., Nucleic Acids Res., mutation is to be detected, except that a predetermined 25:1999-2004 (1997); Whitcombe et al., Clin. Chem., nucleotide is used at the variant locus. Upon annealing the 44:918-923 (1998). probe to the target DNA to form a duplex, the E. coli mutS 0478. In addition, the detection in the present invention protein is contacted with the duplex. Since the mutS protein can also employ a chemiluminescence-based technique. For binds only to heteroduplex sequences containing a nucle example, an oligonucleotide probe can be designed to otide mismatch, the binding of the mutS protein will be hybridize to either the wild-type or a variant TLK1, WARS2, indicative of the presence of a mutation. See Modrich et al., ARTS2, MSR, AKAP9, DNAJD1, GOLPH4, RABEP1, Ann. Rev. Genet., 25:229-253 (1991). TAP2, NARG2, DDX58, CD39, FKBP1a, SRI, XRRA1, 0476 A great variety of improvements and variations IRF5 or AMFR gene locus but not both. The probe is labeled have been developed in the art on the basis of the above with a highly chemiluminescent acridinium ester. Hydroly described basic techniques, and can all be useful in detecting sis of the acridinium ester destroys chemiluminescence. The mutations or nucleotide variants in the present invention. hybridization of the probe to the target DNA prevents the For example, the “sunrise probes’ or “molecular beacons' hydrolysis of the acridinium ester. Therefore, the presence or utilize the fluorescence resonance energy transfer (FRET) absence of a particular mutation in the target DNA is property and give rise to high sensitivity. See Wolf et al., determined by measuring chemiluminescence changes. See Proc. Nat. Acad. Sci. USA, 85:8790-8794 (1988). Typically, Nelson et al., Nucleic Acids Res., 24:4998-5003 (1996). a probe spanning the nucleotide locus to be detected are 0479. The detection of genetic variation in the TLK1, designed into a hairpin-shaped structure and labeled with a WARS2, ARTS2, MSR, AKAP9, DNAJD1, GOLPH4, quenching fluorophore at one end and a reporter fluorophore RABEP1, TAP2, NARG2, DDX58, CD39, FKBP1a, SRI, at the other end. In its natural state, the fluorescence from the XRRA1, IRF5 or AMFR gene in accordance with the reporter fluorophore is quenched by the quenching fluoro present invention can also be based on the “base excision phore due to the proximity of one fluorophore to the other. sequence scanning (BESS) technique. The BESS method is Upon hybridization of the probe to the target DNA, the 5' a PCR-based mutation scanning method. BESS T-Scan and end is separated apart from the 3'-end and thus fluorescence BESS G-Tracker are generated which are analogous to Tand signal is regenerated. See Nazarenko et al., Nucleic Acids Gladders of dideoxy sequencing. Mutations are detected by Res., 25:2516-2521 (1997); Rychlik et al., Nucleic Acids comparing the sequence of normal and mutant DNA. See, Res., 17:8543-8551 (1989); Sharkey et al., Bio/Technology e.g., Hawkins et al., Electrophoresis, 20:1171-1176 (1999). 12:506-509 (1994); Tyagi et al., Nat. Biotechnol., 14:303 308 (1996); Tyagi et al., Nat. Biotechnol., 16:49-53 (1998). 0480. Another useful technique that is gaining increased The homo-tag assisted non-dimer system (HANDS) can be popularity is mass spectrometry. See Graber et al., Curr: used in combination with the molecular beacon methods to Opin. Biotechnol., 9:14-18 (1998). For example, in the Suppress primer-dimer accumulation. See Brownie et al., primer oligo base extension (PROBETM) method, a target Nucleic Acids Res., 25:3235-3241 (1997). nucleic acid is immobilized to a solid-phase Support. A primer is annealed to the target immediately 5' upstream 0477 Dye-labeled oligonucleotide ligation assay is a from the locus to be analyzed. Primer extension is carried FRET-based method, which combines the OLA assay and out in the presence of a selected mixture of deoxyribonuce PCR. See Chen et al., Genome Res. 8:549-556 (1998). lotides and dideoxyribonucleotides. The resulting mixture of TaqMan is another FRET-based method for detecting nucle newly extended primers is then analyzed by MALDI-TOF. otide variants. A TaqMan probe can be oligonucleotides designed to have the nucleotide sequence of the TLK1, See e.g., Monforte et al., Nat. Med., 3:360-362 (1997). WARS2, ARTS2, MSR, AKAP9, DNAJD1, GOLPH4, 0481. In addition, the microchip or microarray technolo RABEP1, TAP2, NARG2, DDX58, CD39, FKBP1a, SRI, gies are also applicable to the detection method of the XRRA1, IRF5 or AMFR gene spanning the variant locus of present invention. Essentially, in microchips, a large number interest and to differentially hybridize with different TLK1, of different oligonucleotide probes are immobilized in an WARS2, ARTS2, MSR, AKAP9, DNAJD1, GOLPH4, array on a substrate or carrier, e.g., a silicon chip or glass RABEP1, TAP2, NARG2, DDX58, CD39, FKBP1a, SRI, slide. Target nucleic acid sequences to be analyzed can be XRRA1, IRF5 or AMFR alleles. The two ends of the probe contacted with the immobilized oligonucleotide probes on are labeled with a quenching fluorophore and a reporter the microchip. See Lipshutz et al., Biotechniques, 19:442 fluorophore, respectively. The TaqMan probe is incorporated 447 (1995); Chee et al., Science, 274:610-614 (1996); Kozal into a PCR reaction for the amplification of a target TLK1, et al., Nat. Med. 2:753-759 (1996); Hacia et al., Nat. Genet., WARS2, ARTS2, MSR, AKAP9, DNAJD1, GOLPH4, 14:441-447 (1996); Saiki et al., Proc. Natl. Acad. Sci. USA, RABEP1, TAP2, NARG2, DDX58, CD39, FKBP1a, SRI, 86:6230-6234 (1989); Gingeras et al., Genome Res., 8:435 XRRA1, IRF5 or AMFR gene region containing the locus of 448 (1998). Alternatively, the multiple target nucleic acid interest using Taq polymerase. As Taq polymerase exhibits sequences to be studied are fixed onto a substrate and an 5'-3' exonuclease activity but has no 3'-5' exonuclease activ array of probes is contacted with the immobilized target ity, if the TaqMan probe is annealed to the target TLK1, sequences. See Drmanac et al., Nat. Biotechnol., 16:54-58 US 2007/0O82347 A1 Apr. 12, 2007 48

(1998). Numerous microchip technologies have been devel “flap. Each released “flap' then binds to a fluorescently oped incorporating one or more of the above described labeled probe to form another cleavage structure. When the techniques for detecting mutations. The microchip technolo cleavase enzyme cuts the labeled probe, the probe emits a gies combined with computerized analysis tools allow fast detectable fluorescence signal. See e.g. Lyamichev et al., screening in a large scale. The adaptation of the microchip Nat. Biotechnol., 17:292-296 (1999). technologies to the present invention will be apparent to a person of skill in the art apprised of the present disclosure. 0484 The rolling circle method is another method that See, e.g., U.S. Pat. No. 5,925.525 to Fodor et al; Wilgenbus avoids exponential amplification. Lizardi et al., Nature et al., J. Mol. Med., 77:761-786 (1999); Graber et al., Curr: Genetics, 19:225-232 (1998) (which is incorporated herein Opin. Biotechnol., 9:14-18 (1998); Hacia et al., Nat. Genet., by reference). For example, Sniper'TM, a commercial 14:441-447 (1996); Shoemaker et al., Nat. Genet., 14:450 embodiment of this method, is a sensitive, high-throughput 456 (1996): DeRisi et al., Nat. Genet., 14:457-460 (1996): SNP scoring system designed for the accurate fluorescent detection of specific variants. For each nucleotide variant, Chee et al., Nat. Genet., 14:610-614 (1996); Lockhart et al., two linear, allele-specific probes are designed. The two Nat. Genet., 14:675-680 (1996); Drobyshev et al., Gene, allele-specific probes are identical with the exception of the 188:45-52 (1997). 3'-base, which is varied to complement the variant site. In 0482. As is apparent from the above survey of the suit the first stage of the assay, target DNA is denatured and then able detection techniques, it may or may not be necessary to hybridized with a pair of single, allele-specific, open-circle amplify the target DNA, i.e., the TLK1, WARS2, ARTS2, oligonucleotide probes. When the 3'-base exactly comple MSR, AKAP9, DNAJD1, GOLPH4, RABEP1, TAP2, ments the target DNA, ligation of the probe will preferen NARG2, DDX58, CD39, FKBP1a, SRI, XRRA1, IRF5 or tially occur. Subsequent detection of the circularized oligo AMFR gene or cDNA or mRNA to increase the number of nucleotide probes is by rolling circle amplification, target DNA molecule, depending on the detection tech whereupon the amplified probe products are detected by niques used. For example, most PCR-based techniques combine the amplification of a portion of the target and the fluorescence. See Clark and Pickering, Life Science News 6, detection of the mutations. PCR amplification is well known 2000, Amersham Pharmacia Biotech (2000). in the art and is disclosed in U.S. Pat. Nos. 4,683,195 and 0485. A number of other techniques that avoid amplifi 4,800,159, both which are incorporated herein by reference. cation all together include, e.g., Surface-enhanced resonance For non-PCR-based detection techniques, if necessary, the Raman scattering (SERRS), fluorescence correlation spec amplification can be achieved by, e.g., in vivo plasmid troscopy, and single-molecule electrophoresis. In SERRS, a multiplication, or by purifying the target DNA from a large chromophore-nucleic acid conjugate is absorbed onto col amount of tissue or cell samples. See generally, Sambrook et loidal silver and is irradiated with laser light at a resonant al., Molecular Cloning: A Laboratory Manual, 2" ed., Cold frequency of the chromophore. See Graham et al., Anal. Spring Harbor Laboratory, Cold Spring Harbor, N.Y., 1989. Chem., 69:4703-4707 (1997). The fluorescence correlation However, even with scarce samples, many sensitive tech spectroscopy is based on the spatio-temporal correlations niques have been developed in which Small genetic varia among fluctuating light signals and trapping single mol tions such as single-nucleotide Substitutions can be detected ecules in an electric field. See Eigen et al., Proc. Natl. Acad. without having to amplify the target DNA in the sample. For Sci. USA, 91:5740-5747 (1994). In single-molecule electro example, techniques have been developed that amplify the phoresis, the electrophoretic velocity of a fluorescently signal as opposed to the target DNA by, e.g., employing tagged nucleic acid is determined by measuring the time branched DNA or dendrimers that can hybridize to the target required for the molecule to travel a predetermined distance DNA. The branched or dendrimer DNAS provide multiple between two laser beams. See Castro et al., Anal. Chem., hybridization sites for hybridization probes to attach thereto 67:3181-3186 (1995). thus amplifying the detection signals. See Detmer et al., J. Clin. Microbiol., 34:901-907 (1996); Collins et al., Nucleic 0486 In addition, the allele-specific oligonucleotides Acids Res., 25:2979-2984 (1997); Hornet al., Nucleic Acids (ASO) can also be used in in situ hybridization using tissues Res., 25:4835-4841 (1997); Hornet al., Nucleic Acids Res., or cells as Samples. The oligonucleotide probes which can 25:4842-4849 (1997); Nilsen et al., J. Theor: Biol., 187:273 hybridize differentially with the wild-type gene sequence or 284 (1997). the gene sequence harboring a mutation may be labeled with radioactive isotopes, fluorescence, or other detectable mark 0483. In yet another technique for detecting single nucle ers. In situ hybridization techniques are well known in the otide variations, the Invader(R) assay utilizes a novel linear art and their adaptation to the present invention for detecting signal amplification technology that improves upon the long the presence or absence of a nucleotide variant in the TLK1, turnaround times required of the typical PCR DNA WARS2, ARTS2, MSR, AKAP9, DNAJD1, GOLPH4, sequenced-based analysis. See Cooksey et al., Antimicrobial RABEP1, TAP2, NARG2, DDX58, CD39, FKBP1a, SRI, Agents and Chemotherapy 44:1296-1301 (2000). This assay XRRA1, IRF5 or AMFR gene of a particular individual is based on cleavage of a unique secondary structure formed should be apparent to a skilled artisan apprised of this between two overlapping oligonucleotides that hybridize to disclosure. the target sequence of interest to form a “flap. Each “flap' then generates thousands of signals per hour. Thus, the 0487 Protein-based detection techniques may also prove results of this technique can be easily read, and the methods to be useful, especially when the nucleotide variant causes do not require exponential amplification of the DNA target. amino acid Substitutions or deletions or insertions or frame The Invader(R) system utilizes two short DNA probes, which shift that affect the protein primary, secondary or tertiary are hybridized to a DNA target. The structure formed by the structure. To detect the amino acid variations, protein hybridization event is recognized by a special cleavase sequencing techniques may be used. For example, an TLK1. enzyme that cuts one of the probes to release a short DNA WARS2, ARTS2, MSR, AKAP9, DNAJD1, GOLPH4, US 2007/0O82347 A1 Apr. 12, 2007 49

RABEP1, TAP2, NARG2, DDX58, CD39, FKBP1a, SRI, charts, images or any other visual forms. For example, XRRA1, IRF5 or AMFR protein or fragment thereof can be images of gel electrophoresis of PCR products can be used synthesized by recombinant expression using an TLK1. in explaining the results. Diagrams showing where a variant WARS2, ARTS2, MSR, AKAP9, DNAJD1, GOLPH4, occurs in an individual's TLK1, WARS2, ARTS2, MSR, RABEP1, TAP2, NARG2, DDX58, CD39, FKBP1a, SRI, AKAP9, DNAJD1, GOLPH4, RABEP1, TAP2, NARG2, XRRA1, IRF5 or AMFR DNA fragment isolated from an DDX58, CD39, FKBP1a, SRI, XRRA1, IRF5 or AMFR individual to be tested. Preferably, an TLK1, WARS2, gene are also useful in indicating the testing results. The ARTS2, MSR, AKAP9, DNAJD1, GOLPH4, RABEP1, statements and visual forms can be recorded on a tangible TAP2, NARG2, DDX58, CD39, FKBP1a, SRI, XRRA1, media Such as papers, computer readable media Such as IRF5 or AMFR cDNA fragment of no more than 100 to 150 floppy disks, compact disks, etc., or on an intangible media, base pairs encompassing the polymorphic locus to be deter e.g., an electronic media in the form of email or website on mined is used. The amino acid sequence of the peptide can internet or intranet. In addition, the result with regard to the then be determined by conventional protein sequencing presence or absence of a nucleotide variant or amino acid methods. Alternatively, the recently developed HPLC-mi variant of the present invention in the individual tested can croscopy tandem mass spectrometry technique can be used also be recorded in a Sound form and transmitted through for determining the amino acid sequence variations. In this any suitable media, e.g., analog or digital cable lines, fiber technique, proteolytic digestion is performed on a protein, optic cables, etc., via telephone, facsimile, wireless mobile and the resulting peptide mixture is separated by reversed phone, internet phone and the like. phase chromatographic separation. Tandem mass spectrom 0491 Thus, the information and data on a test result can etry is then performed and the data collected therefrom is be produced anywhere in the world and transmitted to a analyzed. See Gatlin et al., Anal. Chem., 72:757-763 (2000). different location. For example, when a genotyping assay is 0488 Other useful protein-based detection techniques conducted offshore, the information and data on a test result include immunoaffinity assays based on antibodies selec may be generated and cast in a transmittable form as tively immunoreactive with mutant TLK1, WARS2, ARTS2, described above. The test result in a transmittable form thus MSR, AKAP9, DNAJD1, GOLPH4, RABEP1, TAP2, can be imported into the U.S. Accordingly, the present NARG2, DDX58, CD39, FKBP1a, SRI, XRRA1, IRF5 or invention also encompasses a method for producing a trans AMFR proteins according to the present invention. The mittable form of information on the TLK1, WARS2, ARTS2, method for producing such antibodies is described above in MSR, AKAP9, DNAJD1, GOLPH4, RABEP1, TAP2, detail. Antibodies can be used to immunoprecipitate specific NARG2, DDX58, CD39, FKBP1a, SRI, XRRA1, IRF5 or proteins from Solution samples or to immunoblot proteins AMFR genotype of an individual. The method comprises the separated by, e.g., polyacrylamide gels. Immunocytochemi steps of (1) determining the presence or absence of a cal methods can also be used in detecting specific protein nucleotide variant according to the present invention in the polymorphisms in tissues or cells. Other well-known anti TLK1, WARS2, ARTS2, MSR, AKAP9, DNAJD1, body-based techniques can also be used including, e.g., GOLPH4, RABEP1, TAP2, NARG2, DDX58, CD39, enzyme-linked immunosorbent assay (ELISA), radioimmu FKBP1a, SRI, XRRA1, IRF5 or AMFR gene of the indi noassay (RIA), immunoradiometric assays (IRMA) and vidual; and (2) embodying the result of the determining step immunoenzymatic assays (IEMA), including sandwich in a transmittable form. The transmittable form is the assays using monoclonal or polyclonal antibodies. See e.g., product of the production method. U.S. Pat. Nos. 4,376,110 and 4,486,530, both of which are incorporated herein by reference. 0492. The present invention also provides a kit for geno typing TLK1, WARS2, ARTS2, MSR, AKAP9, DNAJD1, 0489. Accordingly, the presence or absence of an TLK1, GOLPH4, RABEP1, TAP2, NARG2, DDX58, CD39, WARS2, ARTS2, MSR, AKAP9, DNAJD1, GOLPH4, FKBP1a, SRI, XRRA1, IRF5 or AMFR gene, i.e., deter RABEP1, TAP2, NARG2, DDX58, CD39, FKBP1a, SRI, mining the presence or absence of one or more of the XRRA1, IRF5 or AMFR nucleotide variant or amino acid nucleotide or amino acid variants of present invention in a variant in an individual can be determined using any of the TLK1, WARS2, ARTS2, MSR, AKAP9, DNAJD1, detection methods described above. GOLPH4, RABEP1, TAP2, NARG2, DDX58, CD39, FKBP1a, SRI, XRRA1, IRF5 or AMFR gene in a sample 0490 Typically, once the presence or absence of an obtained from a patient. The kit may include a carrier for the TLK1, WARS2, ARTS2, MSR, AKAP9, DNAJD1, various components of the kit. The carrier can be a container GOLPH4, RABEP1, TAP2, NARG2, DDX58, CD39, or Support, in the form of, e.g., bag, box, tube, rack, and is FKBP1a, SRI, XRRA1, IRF5 or AMFR nucleotide variant optionally compartmentalized. The carrier may define an or an amino acid variant resulting from a nucleotide variant of the present invention is determined, physicians or genetic enclosed confinement for safety purposes during shipment counselors or patients or other researchers may be informed and storage. The kit also includes various components useful of the result. Specifically the result can be cast in a trans in detecting nucleotide or amino acid variants discovered in mittable form that can be communicated or transmitted to accordance with the present invention using the above other researchers or physicians or genetic counselors or discussed detection techniques. patients. Such a form can vary and can be tangible or 0493. In one embodiment, the detection kit includes one intangible. The result with regard to the presence or absence or more oligonucleotides useful in detecting one or more of of a TLK1, WARS2, ARTS2, MSR, AKAP9, DNAJD1, the nucleotide variants in TLK1, WARS2, ARTS2, MSR, GOLPH4, RABEP1, TAP2, NARG2, DDX58, CD39, AKAP9, DNAJD1, GOLPH4, RABEP1, TAP2, NARG2, FKBP1a, SRI, XRRA1, IRF5 or AMFR nucleotide variant DDX58, CD39, FKBP1a, SRI, XRRA1, IRF5 or AMFR of the present invention in the individual tested can be gene. Preferably, the oligonucleotides are allele-specific, embodied in descriptive statements, diagrams, photographs, i.e., are designed such that they hybridize only to a mutant US 2007/0O82347 A1 Apr. 12, 2007 50

TLK1, WARS2, ARTS2, MSR, AKAP9, DNAJD1, ligands and antibodies, etc. See Jablonski et al., Nucleic GOLPH4, RABEP1, TAP2, NARG2, DDX58, CD39, Acids Res., 14:6115-6128 (1986); Nguyen et al., Biotech FKBP1a, SRI, XRRA1, IRF5 or AMFR gene containing a niques, 13:116-123 (1992); Rigby et al., J. Mol. Biol., particular nucleotide variant discovered in accordance with 113:237-251 (1977). Alternatively, the oligonucleotides the present invention, under Stringent conditions. Thus, the included in the kit are not labeled, and instead, one or more oligonucleotides can be used in mutation-detecting tech markers are provided in the kit so that users may label the niques such as allele-specific oligonucleotides (ASO), oligonucleotides at the time of use. allele-specific PCR, TaqMan, chemiluminescence-based 0496. In another embodiment of the invention, the detec techniques, molecular beacons, and improvements or tion kit contains one or more antibodies selectively immu derivatives thereof, e.g., microchip technologies. The oligo noreactive with certain TLK1, WARS2, ARTS2, MSR, nucleotides in this embodiment preferably have a nucleotide AKAP9, DNAJD1, GOLPH4, RABEP1, TAP2, NARG2, sequence that matches a nucleotide sequence of a variant DDX58, CD39, FKBP1a, SRI, XRRA1, IRF5 or AMFR TLK1, WARS2, ARTS2, MSR, AKAP9, DNAJD1, proteins or polypeptides containing specific amino acid GOLPH4, RABEP1, TAP2, NARG2, DDX58, CD39, FKBP1a, SRI, XRRA1, IRF5 or AMFR gene allele contain variants discovered in the present invention. Methods for ing a nucleotide variant to be detected. The length of the producing and using such antibodies have been described oligonucleotides in accordance with this embodiment of the above in detail. invention can vary depending on its nucleotide sequence and 0497 Various other components useful in the detection the hybridization conditions employed in the detection pro techniques may also be included in the detection kit of this cedure. Preferably, the oligonucleotides contain from about invention. Examples of Such components include, but are 10 nucleotides to about 100 nucleotides, more preferably not limited to, Taq polymerase, deoxyribonucleotides, from about 15 to about 75 nucleotides, e.g., contiguous span dideoxyribonucleotides other primers suitable for the ampli of 18, 19, 20, 21, 22, 23, 24 or 25 to 21, 22, 23, 24, 26, 27, fication of a target DNA sequence, RNase A, mutS protein, 28, 29 or 30 nucleotide residues of a TLK1, WARS2, and the like. In addition, the detection kit preferably includes ARTS2, MSR, AKAP9, DNAJD1, GOLPH4, RABEP1, instructions on using the kit for detecting nucleotide variants TAP2, NARG2, DDX58, CD39, FKBP1a, SRI, XRRA1, in TLK1, WARS2, ARTS2, MSR, AKAP9, DNAJD1, IRF5 or AMFR nucleic acid one or more of the residues GOLPH4, RABEP1, TAP2, NARG2, DDX58, CD39, being a nucleotide variant of the present invention, i.e., FKBP1a, SRI, XRRA1, IRF5 or AMFR gene sequences. selected from Table 1. Under most conditions, a length of 18 to 30 may be optimum. In any event, the oligonucleotides 7. Use of Genotyping in Diagnostic Applications should be designed such that it can be used in distinguishing one nucleotide variant from another at a particular locus 0498 All of the SNPs of the present invention can be under predetermined stringent hybridization conditions. used to predict whether or not specific genes exhibit altered Preferably, a nucleotide variant is located at the center or levels of expression in individual patients. As such, they all within one (1) nucleotide of the center of the oligonucle have utility in a variety of applications beyond those spe otides, or at the 3' or 5' end of the oligonucleotides. The cifically described below. In particular, the SNPs can be used hybridization of an oligonucleotide with a nucleic acid and to catagorize patient populations into population Subgroups the optimization of the length and hybridization conditions based upon the relative level of gene expression associated with a particular SNP. For example, patents can be classified should be apparent to a person of skill in the art. See as normal-expressors, when they exhibit average or inter generally, Sambrook et al., Molecular Cloning. A Labora mediate levels of gene expression; over-expressors, when tory Manual, 2" ed., Cold Spring Harbor Laboratory, Cold they exhibit increased levels of gene expression; or under Spring Harbor, N.Y., 1989. Notably, the oligonucleotides in expressors, when they exhibit reduced levels of gene expres accordance with this embodiment are also useful in mis Sion. These categories or patient population Sub-groupings match-based detection techniques described above, Such as can be useful when evaluating the effect that altered gene electrophoretic mobility shift assay, RNase protection assay, expression has on particular physiological or pharmacoki mutS assay, etc. netic parameters, or selecting patients for clinical trials for 0494. In another embodiment of this invention, the kit therapeutic treatments. includes one or more oligonucleotides Suitable for use in detecting techniques such as ARMS, oligonucleotide liga 0499. In those situations where a protein being expressed tion assay (OLA), and the like. The oligonucleotides in this directly plays a critical biological role in the human body, embodiment include a TLK1, WARS2, ARTS2, MSR, assessment of an individual’s genotype at a SNP associated AKAP9, DNAJD1, GOLPH4, RABEP1, TAP2, NARG2, with altered levels of expression of the gene encoding this DDX58, CD39, FKBP1a, SRI, XRRA1, IRF5 or AMFR protein may prove more efficient, economical, and more gene sequence of about 10 to about 100 nucleotides, pref reliably predictive, than assays designed to detect the gene erably from about 15 to about 75 nucleotides, e.g., contigu product (e.g., mRNA or protein) itself. One can readily ous span of 18, 19, 20, 21, 22, 23, 24 or 25 to 21, 22, 23, 24, envision large-scale screens of SNPs associated with altered 26, 27, 28, 29 or 30 nucleotide residues immediately 5' levels of gene expression being conducted for multiple upstream from the nucleotide variant to be analyzed. The 3' genes on a single microchip designed to simultaneously end nucleotide in Such oligonucleotides is a nucleotide assess the expression of a large number of genes whose variant in accordance with this invention. products are known to be involved in increased risk of a 0495. The oligonucleotides in the detection kit can be particular undesirable phenotype. labeled with any suitable detection marker including but not 0500 For example, where a protein being expressed limited to, radioactive isotopes, fluorephores, biotin, plays a role in some aspect of drug metabolism, including, enzymes (e.g., alkaline phosphatase), enzyme substrates, for example, detoxification, secretion or excretion, assess US 2007/0O82347 A1 Apr. 12, 2007

ment of an individual’s genotype at a SNP associated with SNPs and/or haplotypes are particularly useful in predicting altered levels of expression of the gene encoding this protein the level of TLK1 gene expression in an individual. may prove more efficient, economical, and more reliably 0507 Thus, in one aspect, the present invention encom predictive, than assays designed to detect the effects of the passes a method for predicting or detecting cancer Suscep gene product (e.g., enzyme). Such as altered pharmacoki tibility in an individual, which comprises the step of geno netic profiles, rapid excretion, reduced efficacy of the drug, typing the individual to determine the individual’s genotype etc. at one or more of the TLK1 loci identified in the present 0501 Additionally, when the relative level of expression invention, namely EX7(a)--63, EX7(a)+190, EX11(a).51 and of a particular set of genes can be predicted by the presence EX25(a)855; or, at another locus at which the genotype is in or absence of a particular SNP, diagnostic assays designed to linkage disequilibrium with one of the SNPs of the present assess the expression levels of the specific individual genes invention. Thus, if one or more the EX7(a)--63 A, EX7(a)-- becomes superflouous, since detection of a single SNP 190C, EX11(a).51G and EX25(a)855A are detected, or a SNP would prove more economical or informative than the that is in linkage disequilibrium with any one of such SNPs quantitiative analysis of expression of the individual genes is detected in the individual, then it can be reasonably at the mRNA or protein level. Such a situation would be predicted that there is an increased likelihood that the expected when the single SNP being genotyped is associated individual will have an increased level of chromosome with the level of expression of a transcription factor, whose missegregation and aneuploidy and, thus, is at an increased over-expression would result in increased transcription of a risk of developing cancer. In particular, if an individual is multiplicity of genes. homozygous with the TLK1 genotype EX7(a)--63A/A, EX7(a)--190C/C, EX11(a)51G/G and/or EX25(a)855A/A, 0502. When selecting patients to be included in clinical then it can be reasonably predicted that the individual has an trails of candidate drug compounds, the SNPs of the instant elevated Susceptibility to chromosome missegregation and invention can be used to decide which patients to enroll in aneuploidy. In other words, such an individual has an the trials, and which patients to exclude. The SNPs could increased likelihood or is at an increased risk of developing also be used to determine which patients should be included cancer. If an individual is heterozygous, then his or her risk in particular dosage regimes within a clinical trial. For of developing cancer is at an intermediate level. On the other example, if the SNP is associated with expression levels of hand, if the individual is homozygous with the TLK1 a gene involved in the metabolism of the candidate drug, genotype EX7(a)+63G/G, EX7(a)--190T/T, EX11(a)51A/A patients that are categorized as over-expressors could be and/or EX25(a)855G/G, then it can be reasonably predicted intentionally placed in higher dosage regimes, than those that the individual has a reduced susceptibility to cancer. identified as under-expressors. Alternatively, if the individual is homozygous with a geno 0503) Similarly, the SNPs of the instant invention can type at a TLK1 locus that is in the same haplotype with the provide critically useful information, which can be used to SNPs EX7(a)+63A, EX7(a)--190C, EX11(a)51G and/or assist health practitioners in making decisions about the EX25(a)855A (in linkage disequilibrium), then it can rea method and course of treatment to be given to specific sonably be predicted that the individual has an increased patients. The information provided by these SNPs can, for Susceptibility to cancer. example, direct the practitioner to choose one particular type 0508. In another aspect of the present invention, a of drug over another. In other words, the information pro method is provided for predicting Susceptibility to diseases vided by these SNPs can be used to direct qualititative associated with DNA damage including, but not limited to, decisions for treatment. Additionally, the information pro heart disease and cancer. This method comprises genotyping vided by these SNPs can be used to direct quantitative the individual at one of more of the TLK1 loci identified in decisions for treatment of patients, such as the dosage to be the present invention, namely EX7(a)--63, EX7(a)--190, given, the frequency with which it is given, and even the EX11(a).51 and/or EX25(a)855, or another locus at which the route by which the dosage is to be administered. genotype is in linkage disequilibrium with one of the SNPs of the present invention. Thus, if one or more of the SNPs 0504 The SNPs of the instant invention can also be used EX7(a)--63G, EX7(a)--190T, EX11(a)51A or EX25(a)855G to predict physiologic or pharmacokinetic consequences of are detected, than it can be reasonably predicted that the treatment with a specific drug at a specific dosage. individual has an increased susceptibility to cancer. Specifi 0505 Specific diagnostic and prognostic applications for cally, if the individual is homozygous with the TLK1 the SNPs of the present invention will now be discussed. genotype EX7(a)+63G/G, EX7(a)--190T/T, EX11(a)51A/A or EX25(a)855G/G, it can be reasonably predicted that the TLK1 individual has an elevated susceptibility to DNA damage 0506) As indicated in Tables 1, 2 or 3 and Tables 36 and Such as that caused by ionizing radiation. If the individual is 37, the expression level of the TLK1 gene in human cells is heterozygous, it can be predicted the individual will have an an inheritable “quantitative trait” with genetic determinants. intermediate susceptibility to cancer. On the other hand, if Furthermore, the SNPs and/or haplotypes in accordance the individual is homozygous with the TLK1 genotype with the present invention are associated with the "quanti EX7(a)--63G/G, EX7(a)--190T/T, EX11(a)51A/A and/or tative trait”, i.e., the TLK1 mRNA level in human cells. EX25(a)855G/G, then it can be reasonably predicted that the Specifically, the SNPs EX7(a)--63A, EX7(a)--190C, individual has a reduced Susceptibility to cancer, especially EX11(a)51G and EX25(a)855A of TLK1 are associated with those associated with DNA damage. a “low expression phenotype' while the EX7(a)--63G, 0509. In yet another aspect, the present invention pro EX7(a)--190T, EX11(a)51A and EX25(a)855G of TLK1 are vides a method of predicting patient and tumor response to associated with a "high expression phenotype.” Thus, the cancer treatment. Although some normal cells are affected US 2007/0O82347 A1 Apr. 12, 2007 52 by radiation, most normal cells appear to recover more fully to developing a secondary cancer as a result of treatment from the effects of radiation than do cancer cells. In accor using DNA-damaging therapy. dance with the present invention, the TLK1 gene of a patient 0512 Particularly, if a patient is homozygous with the in need of radiation treatment is sequenced to determine the TLK1 genotype EX7(a)+63G/G, EX7(a)+190T/T, genotype at one or more of the SNPs or haplotypes of the EX11(a)51A/A and EX25(a)855G/G, then the patient has a present invention, specifically mainly EX7(a)--63, EX7(a)-- higher resistance to DNA-damaging therapy, Such as treat 190, EX11(a).51 and EX25(a)855, or another locus at which ment with ionizing radiation. Conversely, if the patient is the genotype is in linkage disequilibrium with any one of the homozygous with the TLK1 genotype EX7(a)--63A/A, SNPs of the present invention. Expression levels of TLK1 EX7(a)--190C/C, EX11(a)51G/G and EX25(a)855A/A, then can be utilized to predict the effectiveness of treatment in a the patient has an increased Susceptibility to secondary patient, and the ability of the patient to recover from the cancers caused by the primary cancer treatment with DNA radiation therapy treatment itself. If one or more of the SNPs damaging therapy, such as treatment with ionizing radiation. EX7(a)--63G, EX7(a)+190T, EX11(a)51A and EX25(a)855G are detected in the patients genome, or a SNP that is in 0513. In another aspect of the present invention, a linkage disequilibrium with any one of such SNPs is method is provided for predicting or detecting Susceptibility detected in an individual, then it can be reasonably predicted to metabolic disorders such as diabetes, insulin resistance, that the patient is likely to recover more rapidly from the Hermansky-Pudlak syndrome and ARC syndrome in an DNA damaging radiation therapy treatment. In short, the individual, comprising determining the genotype of an indi individual will likely have a shorter recovery time from the vidual at one TLK1 loci identified in the present invention, treatment. On the other hand, where an individual has the namely EX7(a)--63, EX7(a)--190, EX11(a).51 and TLK1 genotype EX7(a)--63A/A, EX7(a)--190C/C, EX25(a)855; or, at another locus which is in linkage dis EX11(a)51A/A and EX25(a)855G/G, then it can be reason equilibrium with one of the SNPs or haplotypes of the ably predicted that the individual will a slower recovery present invention. Thus, if one or more the TLK1 SNPs from cancer treatments involving DNA damage. Such as EX7(a)--63G, EX7(a)+190T, EX11(a)51A and EX25(a)855G radiation therapy. are detected, or a SNP that is in linkage disequilibrium with any one of such SNPs is detected in the individual, then it 0510 While the above discussion relates to the expected can be reasonably predicted that the individual is at an recovery of the patient from the DNA damaging radiation increased risk of developing a metabolic disorder Such as therapy, it is necessary to determine the TLK1 genotype of diabetes or insulin resistance. Particularly, if an individual is the cancerous growth in order to predict the likely efficacy homozygous with the TLK1 genotype EX7(a)--63A/A, of radiation treatment in killing the cancer, since increased EX7(a)--190C/C, EX11(a)51G/G and EX25(a)855A/A, it can TLK1 expression by a tumor would be expected to result in be reasonably predicted that the individual will have an increased resistance of the tumor to the DNA damaging increased Susceptibility to metabolic disorders such as dia treatment. In the event that the cancerous growth has the betes and insulin resistance. An individual that is heterozy TLK1 genotype EX7(a)+63G/G, EX7(a)+190T/T, gous will have an intermediate risk of developing metabolic EX11(a)51G/G and EX25(a)855A/A, it can be reasonably disorders. On the other hand, if an individual is homozygous predicted that the cancer will have a decreased response to with the TLK1 genotype EX7(a)--63G/G, EX7(a)+190T/T, radiation therapy. If the cancerous growth is heterozygous, EX11(a)51A/A and EX25(a)855G/G, it can be predicted that it can be predicted that the cancer will have an intermediate an individual will have a decreased susceptibility to meta response to treatment. On the other hand, where the cancer bolic disorders such as diabetes, insulin resistance, Herman ous growth has the TLK1 genotype EX7(a)--63A/A, EX7(a)-- sky-Pudlak syndrome and ARC syndrome. 190C/C, EX11(a).51A/A and EX25(a)855G/G, then it can be reasonably predicted that the cancerous growth will have an 0514) The SNPs listed in Table 3, i.e. those at positions increased sensitivity to cancer treatment involving DNA 171,620,667, 171,622,696, 171,622,741 and 171,840,599 of damage, and treatment by ionizing radiation would be chromosome II, have also been shown to be associated with expected to be more effective at killing the cancer. altered TLK1 mRNA levels. Chromosome II SNPs associ ated with lower TLK1 mRNA expression levels are 171, 0511) Another aspect of the present invention provides a 620,667G, 171,622,696G, 171,622,741C and method of predicting the risk of DNA-damaging therapy in 171,840,599G, whereas those associated with higher TLK1 creating new cancer, especially leukemia. This method com mRNA expression are 171,620,667A, 171,622,696A, 171, prises the step of genotyping the patient to determine the 622,741T and 171,840,599A. In addition to the SNPs patient’s genotype at one or more of the TLK1 loci specified described above, these chromosome II SNPs may be utilized in the present invention; specifically EX7(a)--63, EX7(a)-- in the applications, as described above. 190, EX11(a).51 and EX25(a)855, or another locus at which the genotype is in linkage disequilibrium with one of the WARS2 SNPs or haplotypes of the present invention. Thus, if one or 0515. As indicated in Table 4 above and Table 38 and 39 more of the SNPs EX7(a)--63G, EX7(a)+190T, EX11(a)51A below, the expression level of the WARS2 gene in human and EX25(a)855G are detected in a patient, it can be pre cells is an inheritable “quantitative trait” with genetic deter dicted that the patient will have an increased DNA-damag minants. Furthermore, the WARS2 gene SNPs in accordance ing therapy, and would be less likely to develop a new with the present invention are associated with the "quanti cancer, such as leukemia, as a result of the DNA-damaging tative trait”, i.e., the WARS2 mRNA level in human cells. therapy used to treat the initial cancer. Alternatively, if one Specifically, the WARS2 SNPs EX1(a)-963G, EX1(a)-103T, or more of the SNPs EX7(a)--63A, EX7(a)--190C, EX6(a)780G, EX6(a)842T and EX6(a)2152G are associated EX11(a)51G and EX25(a)855A are present in the patient, it with a “low expression phenotype' while the EX1(a)-963 A, can be predicted that the individual will be more susceptible EX1(a)-103C, EX6(a)780A, EX6(a)842G and EX6(a)2152A US 2007/0O82347 A1 Apr. 12, 2007

SNPs are associated with a “high expression phenotype.” can be reasonably predicted that the individual has a reduced Thus, the WARS2 SNPs are particularly useful in predicting Susceptibility to cardiovascular disease, such as dilated and the level of WARS2 gene expression in an individual. hypertrophic cardiomyopathy, cardiac conduction defects, 0516. Thus, in one aspect, the present invention encom Sudden death, ischemic and alcoholic cardiomyopathy, and passes a method for predicting or detecting Susceptibility to myocarditis. neurodegenerative disease in an individual, which comprises 0518. In another aspect, the present invention provides a the step of genotyping the individual to determine the method for predicting or detecting cancer Susceptibility in an individual’s genotype at one or more of the WARS2 loci individual, comprising the step of genotyping the individual identified in the present invention, namely EX1(a)-963, to determine the individual’s genotype at one or more of the EX1(a)-103, EX6(a)780, EX6(a)842 or EX6(a)2152; or, at WARS2 loci identified in the present invention, namely another locus at which the genotype is in linkage disequi EX1(a)-963, EX1(a)-103, EX6(a)780, EX6(a842 or librium with one of the SNPs of the present invention. Thus, EX6(a)2152, or another locus at which the genotype is in if one or more the SNPs EX1(a)-963G, EX1(a)-103T, linkage disequilibrium with one of the SNPs of the present EX6(a)780G, EX6(a)842T or EX6(a)2152G are detected, or invention. Thus, if one or more the SNPs EX1(a)-963G, a SNP that is in linkage disequilibrium with any one of such EX1(a)-103T, EX6(a)780G, EX6(a)842T or EX6(a)2152G SNPs is detected in the individual, then it can be reasonably are detected, or a SNP that is in linkage disequilibrium with predicted that the individual is at an increased risk of any one of such SNPs is detected in the individual, then it developing neurodegenerative disease, particularly Frie can be reasonably predicted that the individual is at an dreich's ataxia, Huntington's disease, Alzheimer's disease, increased risk of developing cancer. In particular, if an ALS and Parkinson's disease. In particular, if an individual individual is homozygous with the WARS2 genotype is homozygous with the WARS2 genotype EX1(a)-963G/G, EX1(a)-963G/G, EX1(a)-103T/T, EX6(a)780G/G, EX1(a)-103T/T, EX6(a)780G/G, EX6(a)842T/T or EX6(a)842T/T or EX6(a)2152G/G, then it can be reasonably EX6(a)2 152G/G, then it can be reasonably predicted that the predicted that the individual has an elevated susceptibility to individual has an elevated Susceptibility to neurodegenera cancer. If an individual is heterozygous, then his or her risk tive disease, particularly Friedreich's ataxia, Huntington's of developing cancer is at an intermediate level. One the disease, Alzheimer's disease, ALS and Parkinson's disease. other hand, if the individual is homozygous with the WARS2 If an individual is heterozygous, then his or her risk of genotype EX1(a)-963A/A, EX1(a)-103C/C, EX6(a)780A/A, developing neurodegenerative disease is at an intermediate EX6(a)842G/G or EX6(a)2152A/A, then it can be reasonably level. One the other hand, if the individual is homozygous predicted that the individual has a reduced susceptibility to with the WARS2 genotype EX1(a)-963A/A, EX1(a)-103C/ CaCC. C, EX6(a)780A/A, EX6(a842G/G or EX6(a)2152A/A, then 0519 In yet another aspect, the present invention pro it can be reasonably predicted that the individual has a vides a method for identifying high-risk patients who have reduced Susceptibility to neurodegenerative disease, particu a poor prognosis of cancer, or for the prognosis of cancer, or larly Friedreich's ataxia, Huntington's disease, Alzheimer's predicting/determining the invasiveness and metastatic disease, ALS and Parkinson's disease. potential of tumor in a patient, particularly a cancer patient. 0517. In another aspect, the present invention provides a The individual to be tested can be a healthy person or an method for predicting or detecting Susceptibility to cardio individual diagnosed with cancer. The method comprises the vascular disease in an individual, which comprises the step step of genotyping the individual to determine the individu of genotyping the individual to determine the individuals als genotype at one or more of the WARS2 loci identified genotype at one or more of the WARS2 loci identified in the in the present invention, namely EX1(a)-963, EX1(a)-103. present invention, namely EX1(a)-963, EX1(a)-103. EX6(a)780, EX6(a)842 or EX6(a)2152; or, at another locus at EX6(a)780, EX6(a842 or EX6(a)2152, or another locus at which the genotype is in linkage disequilibrium with one of which the genotype is in linkage disequilibrium with one of the SNPs or haplotypes of the present invention. Thus, if one the SNPs of the present invention. Thus, if one or more the or more the SNPs EX1(a)-963G, EX 1-103T, EX6(a)780G, SNPs EX1(a)-963G, EX1(a)-103T, EX6(a)780G, EX6(a)842T or EX6(a)2152G are detected, or a SNP that is EX6(a)842T or EX6(a)2152G are detected, or a SNP that is in linkage disequilibrium with any one of such SNPs is in linkage disequilibrium with any one of such SNPs is detected in the individual, then it can be reasonably pre detected in the individual, then it can be reasonably pre dicted that when cancer occurs within that individual, it has dicted that the individual is at an increased risk of develop high metastatic potential, that the cancer has poor prognosis, ing cardiovascular disease. Such as dilated and hypertrophic and that the tumor cells are likely to be invasive. In other cardiomyopathy, cardiac conduction defects, Sudden death, words, the individual has an increased likelihood, or is at an ischemic and alcoholic cardiomyopathy, and myocarditis. In increased risk for cancer metastasis. Particularly, if an particular, if an individual is homozygous with the WARS2 individual is homozygous with the WARS2 genotype genotype EX1(a)-963G/G, EX1(a)-103T/T, EX6(a)780G/G, EX1(a)-963G/G, EX1(a)-103T/T, EX6(a)780G/G, EX6(a)842T/T or EX6(a)2152G/G, then it can be reasonably EX6(a)842T/T or EX6(a)2152G/G, then the individual has predicted that the individual has an elevated susceptibility to particular poor prognosis because it is likely that the tumor cardiovascular disease, such as dilated and hypertrophic cells are highly invasive. In other words, the individual has cardiomyopathy, cardiac conduction defects, Sudden death, a Substantially increased likelihood, or is at a Substantially ischemic and alcoholic cardiomyopathy, and myocarditis. If increased risk for cancer metastasis. However, if an indi an individual is heterozygous, then his or her risk of devel vidual is heterozygous with the genotype EX1(a)-963G/A, oping cardiovascular disease is at an intermediate level. One EX1(a)-103T/C, EX6(a)780G/A, EX6(a)842T/G or the other hand, if the individual is homozygous with the EX6(a)2 152G/A, then the individual has an intermediate WARS2 genotype EX1(a)-963A/A, EX1(a)-103C/C, prognosis and that the tumor cells are potentially invasive. EX6(a)780A/A, EX6(a)842G/G or EX6(a)2152A/A, then it Specifically, the individual has an intermediate level of risk US 2007/0O82347 A1 Apr. 12, 2007 54 for cancer metastasis. That is, the risk is greater than a 10G/G, EX9(a)39C/C, EX9(a)+18C/C, EX11(a)59G/G, person having a homozygous WARS2 genotype of EX1(a)- EX12(a)-28G/G, EX 12(a)-7C/C, EX 15(a)88G/G, 963A/A, EX1(a)-103C/C, EX6(a)780A/A, EX6(a)842G/Gor EX 190173A/A, EX19(a)328w/w, EX19(a)885C/C, EX6(a)2152A/A, but is lower than a person having a EX20(a).2105T/T, EX20(a)719T/T or EX20(a) 1038C/C, then homozygous genotype of EX1(a)-963A/A, EX1(a)-103C/C, it can be reasonably predicted that the individual has an EX6(a)780A/A, EX6(a)842G/G or EX6(a)2152A/A. elevated Susceptibility to cancer, particularly skin cancer (e.g., melanoma), lung cancer (e.g., NSCLCs), ovarian can 0520. Thus, if the individual is homozygous with a cer or thyoma. Likewise, if the individual is homozygous WARS2 genotype EX1(a)-963A/A, EX1(a)-103C/C, with an ARTS1 genotype at a locus that is in the same EX6(a)780A/A, EX6(a)842G/G or EX6(a)2152A/A, it can be haplotype with the SNPs EX6(a)126G, EX12(a)44A and reasonably predicted that any tumors in that individual have EX15(a)74A (in linkage disequilibrium), or in the same a low metastatic potential, that the cancer has good prog haplotype (linkage disequilibrium) with the SNPs nosis, and that the tumor cells are not likely to be invasive. EX6(a)149C and EX8(a)-10G, or in the same haplotype That is, the individual does not have an increased likelihood, (linkage disequilibrium) with the SNPs EX9(a)39C, EX9(a)+ or increased risk, of cancer metastasis. 18C, EX11(a)59G, EX12(a)-28G, EX12(a)-7C and ARTS1 EX15(a)88G, or in the same haplotype (linkage disequilib rium) with the SNPs EX19(a)173A, EX19(a)328w, 0521. As indicated in Tables 5-11 and Tables 40-44, the EX19(a)885C and EX20(a).2105T, or in the same haplotype expression level of the ARTS1 gene in human cells is an (linkage disequilibrium) with the SNPs EX20(a)719T and inheritable “quantitative trait” with genetic determinants. EX20(a) 1038C, then it can reasonably be predicted that the Furthermore, the SNPs and/or haplotypes in accordance individual has an elevated susceptibility to cancer. In other with the present invention are associated with the "quanti words, such an individual has an increased likelihood or is tative trait”, i.e., the ARTS1 mRNA level in human cells. at an increased risk of developing cancer. If an individual is Specifically, the SNPs EX1(a)-1125C, EX2(a)397C, heterozygous, then his or her risk of developing cancer is at EX20(a) 1085G, EX6(a)126G, EX12(a)44A, EX15(a)74A, an intermediate level. On the other hand, if the individual is EX6(a)149C, EX8(a)-10G, EX9(a)39C, EX9(a)+18C, homozygous with the ARTS1 genotype EX1(a)-1125T/T. EX 11(a)59G, EX12(a)-28G, EX12(a)-7C, EX15(a)88G, EX2(a)397G/G, EX20(a) 1085A/A, EX6(a)126AJA, EX 190173A, EX19(a)328w, EX19(a)885C, EX20(a).2105T, EX 12(a)44G/G, EX15(a)74G/G, EX6(a) 149T/T, EX8(a)- EX20(a)719T and EX20(a) 1038C are associated with a “low 10A/A, EX9(a)39T/T, EX9(a)+18T/T, EX11(a)59A/A, expression phenotype' while the EX1(a)-1125T. EX 12(a)-28T/T, EX12(a)-7A/A, EX15(a)88C/C, EX2(a)397G, EX20(a) 1085A, EX6(a)126A, EX12(a)44G, EX 190173C/C, EX19(a)328 m/m, EX19(a)885T/T, EX 15(a)74G, EX6(a) 149T, EX8(a)-10A, EX9(a)39T. EX20(a).2105C/C, EX20(a)719C/C or EX20(a) 1038A/A, EX9(a)+18T, EX1(a)59A, EX12(a)-28T, EX12(a)-7A, then it can be reasonably predicted that the individual has a EX 15(a)88C, EX19(a)173C, EX19(a)328m, EX19(a)885T, reduced susceptibility to cancer. Similarly, if the individual EX20(a).2105C, EX20(a)719C and EX20(a)1038A are asso is homozygous with an ARTS1 genotype at a locus that is in ciated with a “high expression phenotype.” Thus, the SNPs the same haplotype with the SNPs EX6(a)126A, and/or haplotypes are particularly useful in predicting the EX12(a)44G and EX15(a)74G (in linkage disequilibrium), or level of ARTS1 gene expression in an individual. in the same haplotype (linkage disequilibrium) with the SNPs EX6(a)149T and EX8(a)-10A, or in the same haplo 0522 Thus, in one aspect, the present invention encom type (linkage disequilibrium) with the SNPs EX9(a)39T. passes a method for predicting or detecting cancer Suscep EX9(a)+18T, EX11(a).59A, EX12(a)-28T, EX12(a)-7A and tibility in an individual, which comprises the step of geno EX15(a)88C, or in the same haplotype (linkage disequilib typing the individual to determine the individual’s genotype rium) with the SNPs EX19(a)173C, EX19(a)328m, at one or more of the ARTS1 loci identified in the present EX19(a)885TC and EX20(a).2105C, or in the same haplotype invention, namely EX1(a)-1125, EX2(a)397, EX20(a)1085, (linkage disequilibrium) with the SNPs EX20(a)719C and EX6(a)126, EX12(a)44, EX15(a)74, EX6(a)149, EX8(a)-10, EX20(a) 1038A, then it can reasonably be predicted that the EX9(a)39, EX9(a)+18, EX11(a)59, EX12(a)-28, EX12(a)-7, individual has a reduced Susceptibility to cancer. EX 15(a)88, EX19(a) 173, EX19(a)328, EX19(a)885, EX20(a).2105, EX20(a)719 or EX20(a) 1038; or, at another 0523. In another aspect, the present invention provides a locus at which the genotype is in linkage disequilibrium with method for identifying high-risk patients who have a poor one of the SNPs or haplotypes of the present invention. prognosis of cancer, or for the prognosis of cancer, or Thus, if one or more the ARTS1 SNPs EX1(a)-1125C, predicting/determining the invasiveness and metastatic EX2(a)397C, EX20(a) 1085G, EX6(a)126G, EX12(a)44A, potential of a tumor in a patient, particularly cancer patient. EX 15(a)74A, EX6(a)149C, EX8(a)-10G, EX9(a)39C, The individual to be tested can be a healthy person or an EX9(a)+18C, EX11(a)59G, EX12(a)-28G, EX12(a)-7C, individual diagnosed of cancer. The method comprises the EX 15(a)88G, EX19(a) 173A, EX19(a)328w, EX19(a)885C, step of genotyping the individual to determine the individu EX20(a).2105T, EX20(a)719T or EX20(a) 1038C are detected, als genotype at one or more of the ARTS1 loci identified in or a SNP that is in linkage disequilibrium with any one of the present invention, namely EX1(a)-1125, EX2(a)397, such SNPs is detected in the individual, then it can be EX20(a) 1085, EX6(a)126, EX12(a)44, EX15(a)74, reasonably predicted that the individual is at an increased EX6(a)149, EX8(a)-10, EX9(a)39, EX9(a)+18, EX11(a)59, risk of developing cancer, particularly skin cancer, lung EX 12(a)-28, EX12(a)-7, EX15(a)88, EX19(a) 173, cancer, ovarian cancer or thyoma. In particular, if an indi EX 190328, EX19(a)885, EX20(a).2105, EX20(a)719 or vidual is homozygous with the ARTS1 genotype EX1(a)- EX20(a) 1038; or, at another locus at which the genotype is 1125C/C, EX2(a)397C/C, EX20(a) 1085G/G, EX6(a)126G/G, in linkage disequilibrium with one of the SNPs or haplo EX12(a)44A/A, EX15(a)74A/A, EX6(a)149C/C, EX8(a)- types of the present invention. US 2007/0O82347 A1 Apr. 12, 2007

0524) Thus, if one or more the ARTS1 SNPs EX1(a)- individual is homozygous with an ARTS1 genotype at a 1125C, EX2(a)397C, EX20(a) 1085G, EX6(a) 126G, locus that is in the same haplotype with the SNPs EX12(a)44A, EX15(a)74A, EX6(a) 149C, EX8(a)-10G. EX6(a)126A, EX12(a)44G and EX15(a)74G (in linkage dis EX9(a)39C, EX9(a)+18C, EX11(a)59G, EX12(a)-28G, equilibrium), or in the same haplotype (linkage disequilib EX 12(a)-7C, EX15(a)88G, EX19(a) 173A, EX19(a)328w, rium) with the SNPs EX6(a)149T and EX8(a)-10A, or in the EX19(a)885C, EX20(a).2105T, EX20(a)719T O same haplotype (linkage disequilibrium) with the SNPs EX20(a) 1038C are detected, or a SNP that is in linkage EX9(a)39T. EX9(a)+18T, EX11(a)59A, EX12(a)-28T, disequilibrium with any one of such SNPs is detected in the EX12(a)-7A and EX15(a)88C, or in the same haplotype individual, then it can be reasonably predicted that cancers (linkage disequilibrium) with the SNPs EX19(a) 173C, occurring within that individual have high metastatic poten EX 190328m, EX19(a)885TC and EX20(a).2105C, or in the tial, that the cancer has poor prognosis, and that the tumor same haplotype (linkage disequilibrium) with the SNPs cells are likely to be invasive. In other words, the individual EX20(a)719C and EX20(a) 1038A, then it can reasonably be has an increased likelihood, or is at an increased risk for predicted that tumors occurring within this individual have cancer metastasis. Particularly, if an individual is homozy a low metastatic potential, that the cancer has good prog gous with the ARTS1 genotype EX1(a)-1125C/C, nosis, and that the tumor cells are likely not invasive. In EX2(a)397C/C, EX20(a) 1085G/G, EX6(a)126G/G, other words, the individual does not have an increased EX12(a)44A/A, EX15(a)74A/A, EX6(a)149C/C, EX8(a)- likelihood, or increased risk for cancer metastasis. 10G/G, EX9(a)39C/C, EX9(a)+18C/C, EX11(a)59G/G, EX12(a)-28G/G, EX 12(a)-7C/C, EX 15(a)88G/G, 0526 In another aspect, the present invention encom EX 190173A/A, EX19(a)328w/w, EX19(a)885C/C, passes a method for predicting or detecting Susceptibility in EX20(a).2105T/T, EX20(a)719T/T or EX20(a) 1038C/C, then an individual to cardiovascular disease, which comprises the the individual has particularly poor prognosis and the tumor step of genotyping the individual to determine the individu cells are likely highly invasive. In other words, the indi als ARTS1 genotype at one or more of the loci identified in vidual has a Substantially increased likelihood, or is at a the present invention, namely EX1(a)-1125, EX2(a)397, Substantially increased risk from cancer metastasis. How EX20(a) 1085, EX6(a)126, EX12(a)44, EX15(a)74, ever, if an individual is heterozygous with the ARTS1 EX6(a)149, EX8(a)-10, EX9(a)39, EX9(a)+18, EX11(a)59, genotype EX1(a)-1125T/C, EX2(a)397C/G, EX20(a)1085G/ EX 12(a)-28, EX12(a)-7, EX15(a)88, EX19(a) 173, A, EX6(a)126G/A, EX12(a)44G/A, EX15(a)74G/A, EX 190328, EX19(a)885, EX20(a).2105, EX20(a)719 or EX6(a)149T/C, EX8(a)-10G/A, EX9(a)39C/T, EX9(a)+18T/ EX20(a) 1038; or, at another locus at which the genotype is C, EX11(a)59G/A, EX12(a)-28G/T, EX12(a)-7C/A, in linkage disequilibrium with one of the SNPs or haplo EX 15(a)88G/C, EX 190173C/A, EX19(a)328w/m, types of the present invention. Thus, if one or more the SNPs EX19(a)885C/T, EX20(a).2105T/C, EX20(a)719T/C or EX1(a)-1125C, EX2(a)397C, EX20(a) 1085G, EX6(a)126G, EX20(a) 1038A/C, then the individual has poor prognosis EX12(a)44A, EX15(a)74A, EX6(a) 149C, EX8(a)-10G. and the tumor cells are likely invasive. Specifically, the EX9(a)39C, EX9(a)+18C, EX11(a)59G, EX12(a)-28G, individual has an intermediate level of risk of cancer EX 12(a)-7C, EX15(a)88G, EX198173A, EX19(a)328w, metastasis. That is, the risk is greater than a person having EX19(a)885C, EX20(a).2105T, EX20719T or EX20(a)1038C a homozygous ARTS1 genotype of EX1(a)-1125T/T. are detected, or a SNP that is in linkage disequilibrium with EX2(a)397G/G, EX20(a) 1085A/A, EX6(a)126AJA, any one of such SNPs is detected in the individual, then it EX 12(a)44G/G, EX15(a)74G/G, EX6(a) 149T/T, EX8(a)- can be reasonably predicted that the individual is at an 10A/A, EX9(a)39T/T, EX9(a)+18T/T, EX11(a)59A/A, increased risk of developing a cardiovascular disease, par EX 12(a)-28T/T, EX12(a)-7A/A, EX15(a)88C/C, ticularly high blood pressure, hypertension, cardiac hyper EX19(a) 173C/C, EX19(a)328m/m, EX19(a)885T/T, trophy, myocardial damage or coronary heart disease. Par EX20(a).2105C/C, EX20(a)719C/C or EX20(a) 1038A/A, but ticularly, if an individual is homozygous with the ARTS1 is lower than a person having a homozygous genotype of genotype EX1(a)-1125C/C, EX2(a)397C/C, EX20(a) 1085G/ G, EX6(a)126G/G, EX12(a)44A/A, EX15(a)74A/A, EX1(a)-1125C/C, EX2(a)397C/C, EX20(a) 1085G/G, EX6(a)149C/C, EX8(a)-10G/G, EX9(a)39C/C, EX9(a)+18C/ EX6(a)126G/G, EX12(a)44A/A, EX 15(a)74A/A, C, EX11(a)59G/G, EX12(a)-28G/G, EX12(a)-7C/C, EX6(a)149C/C, EX8(a)-10G/G, EX9(a)39C/C, EX9(a)+18C/ EX 15(a)88G/G, EX 190173A/A, EX 19(a)328w/w, C, EX1(a)59G/G, EX12(a)-28G/G, EX12(a)-7C/C, EX19(a)885C/C, EX20(a).2105T/T, EX20(a)719T/T or EX 15(a)88G/G, EX 190173A/A, EX 190328w/w, EX20(a) 1038C/C, then it can be reasonably predicted that EX19(a)885C/C, EX20(a).2105T/T, EX20(a)719T/T or the individual has an elevated susceptibility to cardiovascu EX20(a) 1038C/C. lar disease, particularly hypertension, cardiac hypertrophy, 0525 Thus, if the individual is homozygous with the myocardial damage and coronary heart disease. Likewise, if ARTS1 genotype EX1(a)-1125T/T, EX2(a)397G/G, the individual is homozygous with a genotype at an ARTS1 EX20(a) 1085A/A, EX6(a)126AJA, EX12(a)44G/G, locus that is in the same haplotype with the SNPs EX 15(a)74G/G, EX6(a) 149T/T, EX8(a)-10A/A, EX9(a)39T/ EX6(a)126G, EX12(a)44A and EX15(a)74A (in linkage dis T, EX9(a)+18T/T, EX11(a)59A/A, EX12(a)-28T/T, equilibrium), or in the same haplotype (linkage disequilib EX12(a)-7A/A, EX15(a)88C/C, EX19(a)173C/C, rium) with the SNPs EX6(a)149C and EX8(a)-10G, or in the EX 190328m/m, EX19(a)885T/T, EX20(a).2105C/C, same haplotype (linkage disequilibrium) with the SNPs EX20(a)719C/C or EX20(a) 1038A/A, then it can be reason EX9(a)39C, EX9(a)+18C, EX11(a)59G, EX12(a)-28G, ably predicted that a tumor occurring within this individual EX12(a)-7C and EX15(a)88G, or in the same haplotype has a low metastatic potential, that the cancer has good (linkage disequilibrium) with the SNPs EX19(a)173A, prognosis, and that the tumor cells are likely not invasive. EX 190328w, EX19(a)885C and EX20(a).2105T, or in the That is, the individual does not have an increased likelihood same haplotype (linkage disequilibrium) with the SNPs or increased risk of cancer metastasis. Similarly, if the EX20(a)719T and EX20(a)1038C, then it can reasonably be US 2007/0O82347 A1 Apr. 12, 2007 56 predicted that the individual has an elevated susceptibility to tion. Likewise, if the individual is homozygous with a cardiovascular disease. In other words, Such an individual genotype at an ARTS1 locus that is in the same haplotype has an increased likelihood, or is at an increased risk for with the SNPs EX6(a)126G, EX12(a)44A and EX15(a)74A developing cardiovascular disease. If an individual is het (in linkage disequilibrium), or in the same haplotype (link erozygous, then his or her risk of developing cardiovascular age disequilibrium) with the SNPs EX6(a)149C and EX8(a)- disease is at an intermediate level. On the other hand, if the 10G, or in the same haplotype (linkage disequilibrium) with individual is homozygous with the ARTS1 genotype the SNPs EX9(a)39C, EX9(a)+18C, EX11(a)59G, EX12(a)- EX1(a)-1125T/T, EX2(a)397G/G, EX20(a) 1085A/A, 28G, EX12(a)-7C and EX15(a)88G, or in the same haplo EX6(a)126AJA, EX12(a)44G/G, EX 15(a)74G/G, type (linkage disequilibrium) with the SNPs EX19(a) 173A, EX6(a)149T/T, EX8(a)-10A/A, EX9(a)39T/T, EX9(a)+18T/ EX 190328w, EX19(a)885C and EX20(a).2105T, or in the T. EX11(a)59A/A, EX12(a)-28T/T, EX12(a)-7A/A, same haplotype (linkage disequilibrium) with the SNPs EX15(a)88C/C, EX19(a) 173C/C, EX19(a)328m/m, EX20(a)719T and EX20(a)1038C, then it can reasonably be EX19(a)885T/T, EX20(a).2105C/C, EX20(a)719C/C or predicted that the individual has a diminished immune EX20(a) 1038A/A, then it can be reasonably predicted that response and decrease resistance to viral infection. How the individual has a reduced susceptibility to cardiovascular ever, if an individual is heterozygous with the genotype disease. Similarly, if the individual is homozygous with a EX1(a)-1125C/T, EX2(a)397C/G, EX20(a) 1085G/A, genotype at an ARTS1 locus that is in the same haplotype EX6(a)126G/A, EX12(a)44G/A, EX 15(a)74G/A, with the SNPs EX6(a)126A, EX12(a)44G and EX15(a)74G EX6(a)149T/C, EX8(a)-10G/A, EX9(a)39C/T, EX9(a)+18T/ (in linkage disequilibrium), or in the same haplotype (link C, EX11(a)59G/A, EX12(a)-28G/T, EX12(a)-7C/A, age disequilibrium) with the SNPs EX6(a)149T and EX8(a)- EX 15(a)88G/C, EX 19(a) 173C/A, EX19(a)328w/m, 10A, or in the same haplotype (linkage disequilibrium) with EX19(a)885C/T, EX20(a).2105T/C, EX20(a)719T/C or the SNPs EX9(a)39T. EX9(a)+18T, EX11(a)59A, EX12(a)- EX20(a) 1038A/C, then the individual has intermediate 28T, EX12(a)-7A and EX15(a)88C, or in the same haplotype immune response. Specifically, the individual has an inter (linkage disequilibrium) with the SNPs EX19(a) 173C, mediate level of risk of viral infection. Alternatively, if the EX 190328m, EX19(a)885TC and EX20(a).2105C, or in the individual is homozygous with the ARTS1 genotype same haplotype (linkage disequilibrium) with the SNPs EX1(a)-1125T/T, EX2(a)397G/G, EX20(a) 1085A/A, EX20(a)719C and EX20(a) 1038A, then it can reasonably be EX6(a)126AJA, EX12(a)44G/G, EX 15(a)74G/G, predicted that the individual has a reduced susceptibility to EX6(a)149T/T, EX8(a)-10A/A, EX9(a)39T/T, EX9(a)+18T/ cardiovascular disease, particularly high blood pressure, T. EX11(a)59A/A, EX12(a)-28T/T, EX12(a)-7A/A, hypertension, cardiac hypertrophy, myocardial damage and EX 15(a)88C/C, EX19(a) 173C/C, EX19(a)328 m/m, coronary heart disease. EX19(a)885T/T, EX20(a).2105C/C, EX20(a)719C/C or EX20(a) 1038A/A, then it can be reasonably predicted that 0527. In another aspect, the present invention provides a the individual will have a good immune response. In other method for predicting/determining immune response and/or word, the individual will have a reduced susceptibility to resistance to viral infection in an individual. The method infection, especially viral infection. Similarly, if the indi comprises the step of genotyping the individual to determine vidual is homozygous with a genotype at an ARTS1 locus the individual’s genotype at one or more of the ARTS1 loci that is in the same haplotype with the SNPs EX6(a)126A, identified in the present invention, namely EX1(a)-1125, EX12(a)44G and EX15(a)74G (in linkage disequilibrium), or EX2(a)397, EX20(a) 1085, EX6(a)126, EX12(a)44, in the same haplotype (linkage disequilibrium) with the EX 15(a)74, EX6(a)149, EX8(a)-10, EX9(a)39, EX9(a)+18, SNPs EX6(a)149T and EX8(a)-10A, or in the same haplo EX 11(a)59, EX12(a)-28, EX12(a)-7, EX15(a)88, type (linkage disequilibrium) with the SNPs EX9(a)39T. EX 190,173, EX19(a)328, EX19(a)885, EX20(a).2105, EX9(a)+18T, EX11(a).59A, EX12(a)-28T, EX12(a)-7A and EX20719 or EX20(a) 1038; or, at another locus at which the EX15(a)88C, or in the same haplotype (linkage disequilib genotype is in linkage disequilibrium with one of the SNPs rium) with the SNPs EX19(a)173C, EX19(a)328m, or haplotypes of the present invention. Thus, if one or more EX19(a)885TC and EX20(a).2105C, or in the same haplotype the SNPs EX1(a)-1125C, EX2(a)397C, EX20(a) 1085G, (linkage disequilibrium) with the SNPs EX20(a)719C and EX6(a)126G, EX12(a)44A, EX15(a)74A, EX6(a) 149C, EX20(a) 1038A, then it can reasonably be predicted that the EX8(a)-10G, EX9(a)39C, EX9(a)+18C, EX11(a)59G, individual will have a normal immune response to infection, EX 12(a)-28G, EX12(a)-7C, EX15(a)88G, EX19(a) 173A, Such as viral infection. EX 190328w, EX19(a)885C, EX20(a).2105T, EX20(a)719T or EX20(a) 1038C are detected, or a SNP that is in linkage 0528. In another aspect, the present invention provides a disequilibrium with any one of such SNPs is detected in the method for predicting and/or determining Susceptibility to individual, then it can be reasonably predicted that the inflammatory and autoimmune disease. The method com individual will have a reduced immune response and thus, a prises the step of genotyping the individual to determine the decreased resistance to viral infection. In other words, the individual’s genotype at one or more of the ARTS1 loci individual has an increased likelihood of developing viral identified in the present invention, namely EX1(a)-1125, infection. Particularly, if an individual is homozygous with EX2(a)397, EX20(a) 1085, EX6(a) 126, EX12(a)44, the ARTS1 genotype EX1(a)-1125C/C, EX2(a)397C/C, EX 15(a)74, EX6(a)149, EX8(a)-10, EX9(a)39, EX9(a)+18, EX20(a) 1085G/G, EX6(a)126G/G, EX12(a)44A/A, EX 11(a)59, EX12(a)-28, EX12(a)-7, EX15(a)88, EX 15(a)74A/A, EX6(a) 149C/C, EX8(a)-10G/G, EX9(a)39C/ EX 190,173, EX19(a)328, EX19(a)885, EX20(a).2105, EX20719 or EX20(a) 1038; or, at another ARTS1 locus which is in linkage disequilibrium with one of the SNPs or haplotypes of the present invention. Thus, if one or more the EX20(a)719T/T or EX20(a) 1038C/C, then the individual has SNPs EX1(a)-1125C, EX2(a)397C, EX20(a) 1085G, particularly poor immune response, especially to viral infec EX6(a)126G, EX12(a)44A, EX15(a)74A, EX6(a) 149C, US 2007/0O82347 A1 Apr. 12, 2007 57

EX8(a)-10G, EX9(a)39C, EX9(a)+18C, EX11(a)59G, same haplotype (linkage disequilibrium) with the SNPs EX 12(a)-28G, EX12(a)-7C, EX15(a)88G, EX19(a) 173A, EX20(a)719C and EX20(a) 1038A, then it can reasonably be EX 190328w, EX19(a)885C, EX20(a).2105T, EX20(a)719T predicted that the individual has a reduced susceptibility to or EX20(a) 1038C are detected, or a SNP that is in linkage autoimmune diseases such as endotoxic shock, TNF-depen disequilibrium with any one of such SNPs is detected in the dent arthritis, and encephalomyelitis. individual, then it can be reasonably predicted that the 0529) The SNPs listed in Table 11, i.e. those at positions individual will have increased susceptibility to autoimmune 96,112,196 and 96,134,750 of chromosome 5, have also disease, particularly endotoxic shock, TNF-dependent been shown to be associated with ARTS1 mRNA levels. arthritis, and encephalomyelitis. Particularly, if an individual Chromosome 5 SNPs associated with lower ARTS1 mRNA is homozygous with the ARTS1 genotype EX1(a)-1 125C/C, expression levels are 96,112, 196C and 96,134,750C, EX2(a)397C/C, EX20(a) 1085G/G, EX6(a)126G/G, whereas those associated with lower ARTS1 mRNA expres EX12(a)44A/A, EX15(a)74A/A, EX6(a)149C/C, EX8(a)- sion are 96,112, 196T and 96,134,750T. In addition to those 10G/G, EX9(a)39C/C, EX9(a)+18C/C, EX11(a)59G/G, mentioned above, these SNPs may be utilized in the appli EX12(a)-28G/G, EX 12(a)-7C/C, EX 15(a)88G/G, cations described above. EX 190173A/A, EX19(a)328w/w, EX19(a)885C/C, EX20(a).2105T/T, EX20(a)719T/T or EX20(a) 1038C/C, then MSR the individual has particularly elevated susceptibility to 0530. As indicated in Table 12 and 45-47 the expression autoimmune disease, especially endotoxic shock, TNF-de level of the MSR gene in human cells is an inheritable pendent arthritis, and encephalomyelitis. Likewise, if the “quantitative trait” with genetic determinants. Furthermore, individual is homozygous with a genotype at an ARTS1 the SNPs in accordance with the present invention are locus that is in the same haplotype with the SNPs associated with the “quantitative trait”, i.e., MSR mRNA EX6(a)126G, EX12(a)44A and EX15(a)74A (in linkage dis levels in human cells. Specifically, the SNPs EX1(a)-674G, equilibrium), or in the same haplotype (linkage disequilib EX1(a) 19C, EX1(a)+129w, EX5(a)123T, EX5(a) 136C, rium) with the SNPs EX6(a)149C and EX8(a)-10G, or in the EX7(a)146G, EX10(a)+83G, EX11(a)+54C, EX14(a)14T, same haplotype (linkage disequilibrium) with the SNPs EX14(a) 106A, EX14(a)142G and EX15(a)686A are associ EX9(a)39C, EX9(a)+18C, EX11(a)59G, EX12(a)-28G, ated with a “low expression phenotype' while the EX1(a)- EX12(a)-7C and EX15(a)88G, or in the same haplotype 74T, EX1(a) 119T EX1(a)+129m, EX5(a)123C, EX5(a) 136T, (linkage disequilibrium) with the SNPs EX19(a)173A, EX7(a)146A, EX10(a)+83A, EX11(a)+54T, EX14(a) 14C, EX19(a)328w, EX19(a)885C and EX20(a)2105T, or in the EX14(a) 106G, EX14(a)142A and EX15(a)686G are associ same haplotype (linkage disequilibrium) with the SNPs ated with a “high expression phenotype.” Thus, the SNPs are EX20(a)719T and EX20(a)1038C, then it can reasonably be particularly useful in predicting the level of MSR gene predicted that the individual has an elevated susceptibility to expression in an individual. autoimmune disease, especially endotoxic shock, TNF-de pendent arthritis, and encephalomyelitis. However, if an 0531. Thus, in one aspect of the invention a method is individual is heterozygous with the ARTS1 genotype provided for predicting or detecting Susceptibility to hyper EX1(a)-1125C/T, EX2(a)397C/G, EX20(a) 1085G/A, homocysteinemia, cardiovascular disease, atherosclerosis, EX6(a)126G/A, EX12(a)44G/A, EX 15(a)74G/A, recurrent arterial and venous thrombosis, premature coro EX6(a)149T/C, EX8(a)-10G/A, EX9(a)39C/T, EX9(a)+18T/ nary artery disease and neural tube defects in an individual, C, EX1(a)59G/A, EX12(a)-28G/T, EX12(a)-7C/A, which comprises the steps of genotyping the individual to EX 15(a)88G/C, EX 190173C/A, EX19(a)328w/m, determine the individuals genotype at one or more loci EX19(a)885C/T, EX20(a).2105T/C, EX20(a)719T/C or identified in the present invention wherein one or more of EX20(a) 1038A/C, then the individual has intermediate prob the SNPs are detected in the individual, then it can be ability of developing and autoimmune disease. Alterna predicted whether the individual has an increased risk of tively, if the individual is homozygous with the ARTS1 developing a metabolic or vascular disease. Thus, if one or genotype EX1(a)-1125T/T, EX2(a)397G/G, EX20(a)1085A/ more the MSR SNPs EX1(a)-674G, EX1119C, EX1(a)+ A, EX6(a)126A/A, EX12(a)44G/G, EX15(a)74G/G, 129w, EX5(a)123T, EX5(a) 136C, EX7(a)146G, EX10(a)+ EX6(a)149T/T, EX8(a)-10A/A, EX9(a)39T/T, EX9(a)+18T/ 83G, EX11(a)+54C, EX14(a)14T, EX14(a) 106A, T. EX11(a)59A/A, EX12(a)-28T/T, EX12(a)-7A/A, EX14(a) 142G or EX15(a)686A are detected, or, a SNP that is EX15(a)88C/C, EX19(a) 173C/C, EX19(a)328m/m, in linkage disequilibrium with any one of such SNPs is EX19(a)885T/T, EX20(a).2105C/C, EX20(a)719C/C or detected in the individual, then it can be reasonably pre EX20(a) 1038A/A, then it can be reasonably predicted that dicted that the individual is at an increased risk of develop the individual will have a decreased likelihood of develop ing disease, particularly hyperhomocysteinemia, cardiovas ing an autoimmune disease, particularly endotoxic shock, cular disease, atherosclerosis, recurrent arterial and venous TNF-dependent arthritis, and encephalomyelitis. Similarly, thrombosis, premature coronary artery disease and neural if the individual is homozygous with an ARTS1 genotype at tube defects. In particular, if an individual is homozygous a locus that is in the same haplotype with the SNPs with the MSR genotype EX1(a)-674G/G, EX1(a) 19C/C, EX6(a)126A, EX12(a)44G and EX15(a)74G (in linkage dis equilibrium), or in the same haplotype (linkage disequilib rium) with the SNPs EX6(a)149T and EX8(a)-10A, or in the same haplotype (linkage disequilibrium) with the SNPs EX15(a)686A/A, or a SNP that is in linkage disequilibrium EX9(a)39T. EX9(a)+18T, EX11(a)59A, EX12(a)-28T, with any one or more of such SNPs, then it can be reason EX12(a)-7A and EX15(a)88C, or in the same haplotype ably predicted that the individual has an increased Suscep (linkage disequilibrium) with the SNPs EX19(a) 173C, tibility to hyperhomocysteinemia, cardiovascular disease, EX 190328m, EX19(a)885TC and EX20(a).2105C, or in the atherosclerosis, recurrent arterial and venous thrombosis, US 2007/0O82347 A1 Apr. 12, 2007

premature coronary artery disease and neural tube defects. In EX14(a) 106G/G, EX14(a)142A/A or EX15(a)686G/G is other words, such an individual has an increased likelihood detected, or is homozygous with a SNP that is in linkage or is at an increased risk of developing disease, particularly disequilibrium with any one or more of such SNPs, then it hyperhomocysteinemia, cardiovascular disease, atheroscle can be reasonably predicted that disease prognosis is favor rosis, recurrent arterial and venous thrombosis, premature able. That is, the individual does not have an increased coronary artery disease and neural tube defects. If an indi likelihood or increased risk of hyperhomocysteinemia, car vidual is heterozygous, then his or her risk of developing the diovascular disease, atherosclerosis, recurrent arterial and disease is at an intermediate level. On the other hand, if the venous thrombosis, premature coronary artery disease and individual is homozygous with the MSR genotype EX1(a)- neural tube defects. 674T/T, EX1(a) 19T/T, EX1(a)+129m/m, EX5(a)123C/C, 0534. In another aspect, the present invention encom EX5(a)136T/T, EX7(a)146A/A, EX10(a)+83A/A, EX11(a)+ passes a method for predicting or detecting cancer Suscep 54T/T, EX14(a) 14C/C, EX14(a) 106G/G, EX14(a)142A/A or tibility in an individual, which comprises the step of geno EX15(a)686G/G, or a SNP that is in linkage disequilibrium typing the individual to determine the individual’s genotype with any one or more of such SNPs, then it can be reason at one or more of the loci identified in the present invention, ably predicted that the individual has a reduced susceptibil or another locus at which the genotype is in linkage dis ity to disease, particularly hyperhomocysteinemia, cardio equilibrium with one of the SNPs of the present invention. vascular disease, atherosclerosis, recurrent arterial and Thus, if one or more the MSR SNPs EX1(a)-674T, venous thrombosis, premature coronary artery disease and EX1(a) 19T, EX1(a)+129m, EX5(a)123C, EX5(a) 136T, neural tube defects. EX7(a)146A, EX10(a)+83A, EX11(a)+54T, EX14(a) 14C, 0532. In another aspect, the present invention provides a EX14(a) 106G, EX14(a)142A or EX15(a)686G is detected, or method for determining the prognosis of a patient having a a SNP that is in linkage disequilibrium with any one of such hyperhomocysteinemia, cardiovascular disease, atheroscle SNPs is detected in the individual, then it can be reasonably rosis, recurrent arterial and venous thrombosis, premature predicted that the individual is at an increased risk of coronary artery disease and neural tube defects. The indi developing cancer, particularly colon cancer. In particular, if vidual to be tested can be a healthy person or previously an individual is homozygous with the MSR genotype diagnosed individual. The method comprises the step of EX 11(a)-674T/T, EX1(a) 19T/T, EX1(a)+129m/m, genotyping the individual to determine the individuals EX5(a)123C/C, EX5(a) 136T/T, EX7(a) 146A/A, EX10(a)+ genotype at one or more of the loci identified in the present 83A/A, EX11(a)+54T/T, EX14(a) 14C/C, EX14(a)106G/G, invention, or another locus at which the genotype is in EX14(a)142A/A or EX15(a)686G/G is detected, or a SNP linkage disequilibrium with one of the SNPs or haplotypes that is in linkage disequilibrium with any one or more of of the present invention. Thus, if one or more the MSR SNPs such SNPs, then it can be reasonably predicted that the EX1(a)-674G, EX1(a)19C, EX1(a)+129w, EX5(a) 123T, individual has an elevated Susceptibility to cancer, particu EX5(a)136C, EX7(a)146G, EX10(a)+83G, EX11(a)+54C, larly colon cancer. In other words. Such an individual has an EX14(a) 14T, EX14(a) 106A, EX14(a)142G or EX15(a)686A increased likelihood or is at an increased risk of developing are detected, or a SNP that is in linkage disequilibrium with cancer, particularly colon cancer. If an individual is het any one of such SNPs is detected in the individual, then it erozygous, then his or her risk of developing cancer is at an can be reasonably predicted that the individual has high intermediate level. On the other hand, if the individual is potential of disease progression and that the prognosis for homozygous with the MSR genotype EX1(a)-674G/G, the individual is poor. In other words, the individual has an EX1(a) 19C/C, EX1(a)+129w/w, EX5(a)123T/T, increased likelihood or an increased risk of developing the EX5(a)136C/C, EX7(a) 146G/G, EX10(a)+83G/G, EX11(a)+ disease and of disease progression. Particularly, if an indi 54C/C, EX14(a)14T/T, EX14(a) 106A/A, EX14(a)142G/G or vidual is homozygous with the MSR genotype EX1(a)- EX15(a)686A/A, then it can be reasonably predicted that the 674G/G, EX1(a) 19C/C, EX1(a)+129w/w, EX5(a)123T/T, individual has a reduced Susceptibility to cancer, particularly EX5(a)136C/C, EX7(a) 146G/G, EX10(a)+83G/G, EX11(a)+ colon cancer. 54C/C, EX14(a)14T/T, EX14(a) 106A/A, EX14(a)142G/G or 0535 In another aspect, the present invention provides a EX15(a)686A/A, or a SNP that is in linkage disequilibrium method for identifying high-risk patients who have cancer with any one or more of such SNPs, then the individual has ous growths with a poor prognosis of recovery, or for particularly poor prognosis and the disease will likely predicting/determining the invasiveness and metastatic progress at an increased rate. In other words, the individual potential of tumors within a patient, particularly cancer has a substantially increased likelihood or a substantially patient, e.g., with non-Small cell lung cancers (NSCLCs). increased risk of disease progression. However, if an indi The individual to be tested can be a healthy person or an vidual is heterozygous with the MSR genotype EX1(a)- individual diagnosed with cancer. In this aspect of the 674T/G, EX1(a) 19T/C, EX1(a)+129m/m, EX5(a)123C/T, invention, the methods comprise the step of genotyping the EX5(a)136T/C, EX7(a) 146G/A, EX10(a)+83G/A, EX11(a)+ cancerous growth within the individual to determine the 54C/T, EX14(a) 14C/T, EX14(a) 106A/G, EX14(a)142G/A or tumors genotype at one or more of the MSR loci identified EX15(a)686A/G, or is heterozygous with a SNP that is in in the present invention, namely those listed above, or linkage disequilibrium with any one or more of such SNPs, another locus at which the genotype is in linkage disequi then the individual has an intermediate prognosis. Specifi librium with one of the SNPs of the present invention. Thus, cally, the individual has an intermediate level of disease if one or more the MSR SNPs EX1(a)-674T, EX1(a) 19T. progression. EX1(a)+129m, EX5(a)123C, EX5(a) 136T, EX7(a) 146A, 0533. Thus, if the individual is homozygous with the EX10(a)+83A, EX11(a)+54T, EX14(a) 14C, EX14(a) 106G, MSR genotype EX1(a)-674T/T, EX1(a) 19T/T, EX1(a)+ EX14(a) 142A or EX15(a)686G are detected, or a SNP that is 129m/m, EX5(a)123C/C, EX5(a) 136T/T, EX7(a)146A/A, in linkage disequilibrium with any one of such SNPs is EX10(a)+83A/A, EX 11(a)+54T/T, EX14(a) 14C/C, detected in the tumor, then it can be reasonably predicted US 2007/0O82347 A1 Apr. 12, 2007 59 that the tumor has high metastatic potential, that the indi 0538 Thus, in one aspect, the present invention encom vidual has poor prognosis, and that the tumor cells are likely passes a method for predicting or detecting cancer Suscep invasive and given to robust growth. In other words, the tibility in an individual, which comprises the step of geno individual has an increased likelihood or an increased risk of typing the individual to determine the individual’s genotype cancer metastasis and further growth. Particularly, if the at one or more of the AKAP9 loci identified in the present tumor is homozygous with the genotype EX1(a)-674T/T. invention, namely EX1(a)63, EX1(a)99, EX2(a)+3. EX1(a) 19T/T, EX1(a)+129m/m, EX5(a)123C/C, EX9(a)459, EX10(a)186, EX15(a)53, EX16(a)-59, EX18(a)- EX5(a)136T/T, EX7(a)146A/A, EX10(a)+83A/A, EX11(a)+ 41, EX23-20, EX26(a)14, EX32(a)+8, EX34(a)-45, 54T/T, EX14(a) 14C/C, EX14(a) 106G/G, EX14(a)142A/A or EX35(a)215, EX35(a)+8, EX39(a) 121, EX44(a)28, EX45(a)- EX15(a)686G/G, then the individual has particular poor 38, EX50(a)+58, EX19(a) 1011, EX19(a)1020, EX19(a) 1033, prognosis and the tumor cells are likely highly invasive and EX36(a) 19, EX40(a)470, EX40(a)910 or EX40(a) 1055, or given to robust growth. In other words, the individual has a another locus at which the genotype is in linkage disequi substantially increased likelihood or a substantially librium with one of the SNPs of the present invention. Thus, increased risk of cancer metastasis and aggressive tumor if one or more of the AKAP9 SNPs EX1(a) 163T, EX1(a)99C, growth. However, if the tumor is heterozygous with the EX2(a)+3A, EX9(a)459G, EX10(a) 186A, EX15(a)53w, genotype EX1(a)-674T/G, EX1(a) 19T/C, EX1(a)+129m/w, EX16(a)-59C, EX18(a)-41T, EX23(a)-20G, EX26(a) 14C, EX5(a)123C/T, EX5(a) 136T/C, EX7(a)146G/A, EX10(a)+ EX32(a)+8C, EX34(a)-45A, EX35(a)2215A, EX35(a)+8A, 83G/A, EX11(a)+54C/T, EX14(a) 14C/T, EX14(a) 106A/G, EX39(a)121C, EX44(a)28A, EX45(a)-38G, EX50(a)+58T, EX14(a) 142G/A or EX15(a)686A/G, then the individual has EX 1901011T, EX19(a)1020A, EX 1901033A, an intermediate prognosis and the tumor cells are potentially EX36(a) 19C, EX40(a)470G, EX40(a)910C or EX40(a) 1055A invasive. Specifically, the individual has an intermediate are detected, or a SNP that is in linkage disequilibrium with level of risk of cancer metastasis and further tumor growth. any one of such SNPs is detected in the individual, then it On the other hand, if the tumor is homozygous with the can be reasonably predicted that the individual is at an genotype EX1(a)-674G/G, EX1(a) 19C/C, EX1(a)+129w/w, increased risk of developing cancer. In particular, if an EX5(a)123T/T, EX5(a)136C/C, EX7(a)146G/G, EX10(a)+ individual is homozygous with the AKAP9 genotype 83G/G, EX11(a)+54C/C, EX14(a)14T/T, EX14(a) 106A/A, EX1(a)63T/T, EX1(a)99C/C, EX2(a)+3A/A, EX9(a)459G/G, EX14(a) 142G/G or EX15(a)686A/A, then it can be reason EX 10(a)186A/A, EX15(a)53w/w, EX16(a)-59C/C, EX18(a)- ably predicted that the tumor in the individual has low 41T/T, EX23(a)-20G/G, EX26(a) 14C/C, EX32(a)+8C/C, metastatic potential, that the patient has good prognosis, and EX34(a)-45A/A, EX35(a)215A/A, EX35(a)+8A/A, that the tumor cells are likely not invasive or robust. That is, EX39(a)121C/C, EX44(a)28A/A, EX45(a)-38G/G, the individual does not have an increased likelihood or EX50(a)+58T/T, EX19(a) 1011T/T, EX19(a)1020A/A, increased risk of cancer metastasis and rapid tumor growth. EX 1901033A/A, EX36(a) 19C/C, EX40(a)470G/G, EX40(a)910C/C or EX40(a) 1055A/A, then it can be reason 0536 The SNP on Chromosome V at position 7,952,909 ably predicted that the individual has an elevated suscepti has also been shown to be associated with MSR mRNA bility to cancer. In other words, such an individual has an levels. The Chromosome V SNP associated with lower MSR increased likelihood or is at an increased risk of developing mRNA expression levels is 7,952.909G, whereas that asso cancer, particularly skin cancer. If an individual is heterozy ciated with higher mRNA expression levels is 7,952.909C. gous, then his or her risk of developing cancer is at an In addition to those mentioned above, these SNPs may be intermediate level. One the other hand, if the individual is utilized in the applications described above. homozygous with the AKAP9 genotype EX1(a)63C/C, AKAP9 EX1(a)99G/G, EX2(a)+3C/C, EX9(a)459T/T, EX10(a)186G/ G, EX15(a).53m/m, EX16(a)-59G/G, EX18(a)-41G/G, 0537. As indicated in Tables 13-14 and 48-55, the expres EX23(a)-20A/A, EX26(a)14T/T, EX32(a)+8T/T, EX34(a)- sion level of the AKAP9 gene in human cells is an inherit 45G/G, EX(a 215G/G, EX(a)+8T/T, EX39(a)121T/T, able "quantitative trait” with genetic determinants. Further EX44(a)28C/C, EX45(a)-38A/A, EX50(a)+58A/A, more, the SNPs in accordance with the present invention are EX 1901011C/C, EX19(a) 1020G/G, EX19(a) 1033G/G, associated with the “quantitative trait”, i.e. mRNA level of EX36(a) 19T/T, EX40(a)470A/A, EX40(a)910T/T or the AKAP9 gene in human cells. Specifically, the SNPs EX40(a) 1055G/G, then it can be reasonably predicted that EX1(a)-63C, EX1(a)99G, EX2(a)+3C, EX9(a)459T. the individual has a reduced susceptibility of developing EX 10(a)186G, EX15(a).53m, EX16(a)-59G, EX18(a)-41G, EX23(a)-20A, EX26(a)14T, EX32(a)+8T, EX34(a)-45G, CaCC. EX35(a)215G, EX35(a)+8T, EX39(a)121T, EX44(a)28C, 0539. In another aspect, the present invention encom EX45(a)-38A, EX50(a)+58A, EX 19(a) 1011C, passes a method for predicting or detecting Susceptibility to EX 1901020G, EX19(a) 1033G, EX36(a) 19T, EX40(a)470A, neurological disorders in an individual, which comprises the EX40(a)910T and EX40(a) 1055G are associated with a “low step of genotyping the individual to determine the individu expression phenotype' while the EX1(a)-63T, EX1(a)99C, als genotype at one or more of the AKAP9 loci identified in EX2(a)+3A, EX9(a)459G, EX10(a) 186A, EX15(a)53w, the present invention, namely EX1(a)63, EX1(a)99, EX2(a)+ EX16(a)-59C, EX18(a)-41T, EX23(a)-20G, EX26(a) 14C, 3, EX9(a)459, EX1(a)186, EX15(a)53, EX16(a)-59, EX32(a)+8C, EX34(a)-45A, EX35(a)215A, EX35(a)+8A, EX18(a)-41, EX23(a)-20, EX26(a)14, EX32(a)+8, EX34(a)- EX39(a)121C, EX44(a)28A, EX45(a)-38G, EX50(a)+58T, 45, EX35(a)215, EX35(a)+8, EX39(a)121, EX44(a)28, EX 1901011T, EX19(a)1020A, EX19(a)1033A, EX45(a)-38, EX50(a)+58, EX19(a) 1011, EX19(a)1020, EX36(a) 19C, EX40(a)470G, EX40(a)910C and EX 1901033, EX36(a) 19, EX40(a)470, EX40(a)910 or EX40(a) 1055A are associated with a “high expression phe EX40(a) 1055, or another locus at which the genotype is in notype.” Thus, the SNPs are particularly useful in predicting linkage disequilibrium with one of the SNPs of the present the level of AKAP9 gene expression in an individual. invention. Thus, if one or more of the AKAP9 SNPs

US 2007/0O82347 A1 Apr. 12, 2007

ably predicted that the individual has an elevated suscepti genotype at one or more of the DNAJD1 loci identified in bility to depression. If an individual is heterozygous, then the present invention, namely SNPs EX1(a)368, EX1(a)527 his or her risk of developing depression is at an intermediate or EX5(a)+72, or another locus at which the genotype is in level. One the other hand, if the individual is homozygous linkage disequilibrium with one of the SNPs of the present with the AKAP9 genotype EX1(a)63C/C, EX1(a)99G/G, invention. Thus, if one or more the DNAJD1 SNPs EX2(a)+3C/C, EX9(a)459T/T, EX 10(a)186G/G, EX1(a)368T, EX1(a)527G or EX5(a)+72m are detected, or a EX15(a).53m/m, EX16(a)-59G/G, EX18(a)-41G/G, SNP that is in linkage disequilibrium with any one of such EX23(a)-20A/A, EX26(a)14T/T, EX32(a)+8T/T, EX34(a)- SNPs is detected in the a cancer patient, then it can be 45G/G, EX(a 215G/G, EX(a)+8T/T, EX39(a)121T/T, reasonably predicted that the patient's tumor has a high EX44(a)28C/C, EX45(a)-38A/A, EX50(a)+58A/A, metastastic potential, that the patient has a poor prognosis, EX 1901011C/C, EX19(a)1020G/G, EX19(a) 1033G/G, and that the tumor cells are likely to be invasive. In other EX36(a) 19T/T, EX40(a)470A/A, EX40(a)910T/T or words, the individual has an increased likelihood, or has an EX40(a) 1055G/G, then it can be reasonably predicted that increased risk, of cancer metastasis. Particularly, if an indi the individual has a reduced susceptibility to depression. vidual is homozygous with the DNAJD1 genotype EX1(a)368T/T, EX1(a)527G/G or EX5(a)+72m/m, then the DNAUD1 individual has particularly poor prognosis, and the tumor 0542. As indicated in Tables 15, 16, 57 and 58, the cells are likely to be highly invasive. In other words, the expression level of the DNAJD1 gene in human cells is an individual has a substantially increased likelihood, or a inheritable “quantitative trait” with genetic determinants. Substantially increased risk for cancer metastasis. However, Furthermore, the SNPs and/or haplotypes in accordance if an individual is heterozygous with the genotype with the present invention are associated with the "quanti EX1(a)368T/C, EX1(a).527G/A or EX5(a)+72m/w, then the tative trait”, i.e., DNAJD1 mRNA levels in human cells. patient has an intermediate prognosis, and their tumor cells Specifically, the SNPs EX1(a)368T, EX1(a).527G and are potentially invasive. Specifically, the individual has an EX5(a)+72m are associated with a “low expression pheno intermediate level of risk of cancer metastasis. That is, the type' while the EX1(a)368C, EX1(a)527A and EX5(a)+72w risk is greater than a person having a homozygous DNAJD1 are associated with a "high expression phenotype.” Thus, the genotype of EX1(a)368C/C, EX1(a)527A/A or EX5(a)+72w/ SNPs and/or haplotypes are particularly useful in predicting w, but is lower than a person having a homozygous genotype the level of DNAJD1 gene expression in an individual. of EX1(a)368T/T, EX1(a)527G/G or EX5(a)+72m/m. 0543. Thus, in one aspect, the present invention encom 0545 Thus, if the individual is homozygous with the passes a method for predicting or detecting cancer Suscep DNAJD1 genotype EX1(a)368C/C, EX1(a)527A/A or tibility in a patient, which comprises the step of genotyping EX5(a)+72w/w, then it can be reasonably predicted that the the individual to determine the individuals genotype at one tumor in the individual has low metastatic potential, that the or more of the DNAJD1 loci identified in the present patient has a good prognosis and that the tumor cells are invention, namely EX1(a)368, EX1527 or EX5(a)+72, or likely not invasive. That is, the individual does not have an another locus at which the genotype is in linkage disequi increased likelihood or increased risk of cancer metastasis. librium with one of these SNPs. Thus, if one or more the 0546. In yet another aspect of the present invention, a DNAJD1 SNPs EX1(a)368T, EX1527G or EX5(a)+72m are method is provided for predicting drug response in a patient detected, or a SNP that is in linkage disequilibrium with any to treatment with one or more anti-tumor agents. Examples one of such SNPs is detected in the individual, then it can be of Such drugs are chemotherapeutics including, but not reasonably predicted that the individual is at an increased limited to pacilitaxel, topotecan and cisplatin. Thus, in risk of developing cancer, particular ovarian cancer. In accordance with the present invention, the DNAJD1 gene of particular, if an individual is homozygous with the DNAJD1 a patient, in need of treatment with an anti-cancer agent, is genotype SNPs EX1(a)368T/T, EX1(a)527G/G or EX5(a)+ genotyped to determine the genotype at one or more of the 72m/m, then it can be reasonably predicted that the indi DNAJD1 loci identified in the present invention, namely vidual has an elevated Susceptibility to cancer, particularly EX1(a)368, EX1(a) 1527 or EX5(a)+72, or another locus at ovarian cancer. In other words, such an individual has an which a genotype is in linkage disequilibrium with one of increased likelihood or is at an increased risk of developing these SNPs. Thus, if one or more the SNPs EX1(a)368C, cancer. If an individual is heterozygous, then his or her risk EX1(a)527A or EX5(a)+72w are detected, or a SNP that is in of developing cancer is at an intermediate level. One the linkage disequilibrium with any one of such SNPs is other hand, if the individual is homozygous with the detected in the individual patient, then it can be reasonably DNAJD1 genotype SNPs EX1(a)368C/C, EX1(a)527A/A or predicted that the individuals cancer is likely to respond to EX5(a)+72w/w, then it can be reasonably predicted that the treatment with an anti-tumor agent. In other words, once an individual has a reduced Susceptibility to cancer, particularly anti-tumor agent is administered, there is an increased ovarian cancer. likelihood that the inhibitor will cause a positive effect in the 0544. In another aspect, the present invention provides a individual, including, e.g., shrinkage or elimination of method for identifying high-risk patients who have cancer tumor, increased death of tumor cells, etc. with a poor prognosis, or for the prognosis of a specific 0547 Particularly, if an individual is homozygous with cancer, or predicting/determining the invasiveness and the DNAJD1 genotype EX1(a)368C/C, EX1(a)527A/A or metastatic potential of a tumor in a patient, particularly EX5(a)+72w/w, then the individual has a substantially cancer patient, e.g., an ovarian cancer patient. The individual increased likelihood of being responsive to treatment with to be tested can be a healthy person or an individual an anti-tumor agent, e.g., paclitaxel, topotecan or cisplatin. diagnosed with cancer. The method comprises the step of If an individual is heterozygous with the genotype genotyping the individual to determine the individuals EX1(a)368C/T, EX1(a)527A/G or EX5(a)+72m/w, then the US 2007/0O82347 A1 Apr. 12, 2007 62 individual is still likely to respond to an anti-tumor agent. anti-tumor agents, particularly chemotherapeutics, such as Specifically, the individual has an intermediate level of pacilitaxel, topotecan or cisplatin. In one embodiment, the responsiveness to anti-tumor agents. That is, the degree of selection of treatment with an anti-tumor agent is based on responsiveness is likely to be greater than that in a person the presence of a homozygous genotype of one or more of having a homozygous genotype of EX1(a)368T/T. the above SNPs. EX1(a)527G/G or EX5(a)+72m/m, but is lower than a person 0551. In yet another aspect of the present invention, a having a homozygous genotype of EX1(a)368C/C, method is provided for selecting candidate human Subjects EX1(a)527A/A or EX5(a)+72w?w. Thus, if the individual is for participation in a clinical trial involving a DNAJD1 homozygous with the DNAJD1 genotype EX1(a)368T/T. inhibitor, which comprises (1) determining, in the DNAJD1 EX1(a)527G/G or EX5(a)+72m/m, then it can be reasonably gene of a tumor sample from an individual patient, the predicted that there is an increased likelihood that the presence or absence of a nucleotide variant that is selected individual exhibits a low responsiveness to treatment with a from the group consisting of EX1(a)368C, EX1(a).527A and anti-tumor agent. EX5(a)+72w, or a SNP that is in linkage disequilibrium with 0548. In specific embodiments, the individual in need of any one of such SNPs, wherein the presence of said nucle an anti-tumor agent is diagnosed as having cancer, e.g., otide variant would indicate that the patient’s tumor is likely ovarian cancer. Also, in certain embodiments, the anti-tumor to respond to a anti-tumor agent, Such as pacilitaxel, topo agent is a chemotherapeutic. In certain examples, such a tecan or cisplatin; and (2) deciding whether to include said chemotherapeutic agents are selected from pacilitaxel, topo individual patient in the clinical trial. For example, if the tecan or cisplatin. patient's tumor has one or more of the nucleotide variants, then clinical trial for an anti-tumor agent may include that 0549. Once the prognosis of a patient’s response to patient, particularly when the patient's tumor is homozygous anti-tumor agent is made, Suitable treatment regimens (e.g., dosage and frequency of administration, and the like) can be in one or more of the SNPs. decided based on the predicted responsiveness of the patient. 0552. In another aspect, the present invention encom For example, if the DNAJD1 gene genotyping result Sug passes a method for predicting or detecting Susceptibility to gests a low responsiveness by the patient to anti-tumor neurodegenerative disease in a patient, which comprises the agent, then a higher dosage of anti-tumor agent would be step of genotyping the individual to determine the individu desirably to the patient, or it may be simply decided that als genotype at one or more of the DNAJD1 loci identified another class of drugs would be more suitable for the patient. in the present invention, namely EX1(a)368, EX1(a)527 and Thus, in another aspect of the invention, a method is EX5(a)+72, or another locus at which the genotype is in provided for determining a dosage of a anti-tumor agent to linkage disequilibrium with any one of these SNPs. Thus, if be administered to a patient, comprising determining the one or more the SNPs EX1(a)368T, EX1(a)527G or EX5(a)+ individual’s genotype at one or more of the DNAJD1 loci 72m are detected, or a SNP that is in linkage disequilibrium identified in the present invention, namely EX1(a)368, with any one of such SNPs is detected in the individual, then EX1(a)527 or EX5(a)+72, or another locus at which the it can be reasonably predicted that the individual has genotype is in linkage disequilibrium with one of these increased risk of neurodegenerative disease, especially SNPs, to determine the likely responsiveness of the patient, Alzheimer's disease, Parkinson's disease, Huntington's dis and determining accordingly the dosage of a anti-tumor ease, prion disorders, CJD. DRPLA, SCA1, SCA3, schizo agent to be administered to the patient, wherein the presence phrenia and depression. In particular, if an individual is of one or more of the SNPs EX1(a)368C, EX1(a).527A or homozygous with the DNAJD1 genotype SNPs EX5(a)+72w, or a SNP that is in linkage disequilibrium with EX1(a)368T/T, EX1(a)527G/G or EX5(a)+72m/m, then it can any one of such SNPs would indicate that the patient is be reasonably predicted that the individual has an elevated likely to respond to said anti-tumor agent at a lower dosage Susceptibility to neurodegenerative disease. In other words, than another patient without the nucleotide variants. In one Such an individual has an increased likelihood or is at an embodiment, the method is used in treating ovarian cancer. increased risk of developing a neurodegenerative disease. If In other embodiments, the method is used in treating breast an individual is heterozygous, then his or her risk of devel cancer, melanoma, lung cancer, brain cancer, neuroblas oping a neurodegenerative disease, particularly, Alzheimer's toma, uterine cancer, leukemia, lymphoma, head and neck disease, Parkinson's disease, Huntington's disease, prion cancer, thyroid cancer, gastrointestinal cancer, pancreatic disorders, CJD. DRPLA, SCA1, SCA3, schizophrenia or cancer, liver cancer, etc. depression is at an intermediate level. One the other hand, if the individual is homozygous with the DNAJD1 genotype 0550. In another aspect of the invention, a method is SNPs EX1(a)368C/C, EX1(a)527A/A or EX5(a)+72w/w, provided for selecting an anti-cancer treatment for a par then it can be reasonably predicted that the individual has a ticular patient's tumor(s), which comprises determining, in reduced Susceptibility to neurodegenerative disease. Such as a DNAJD1 gene from a tumor sample isolated from the Alzheimer's disease, Parkinson's disease, Huntington's dis patient, the presence or absence of a nucleotide variant that ease, prion disorders, CJD. DRPLA, SCA1, SCA3, schizo is selected from the group consisting of EX1(a)368C, phrenia and depression. EX1(a)527A and EX5(a)+72w, or a SNP that is in linkage disequilibrium with any one of such SNPs, wherein the 0553. In another aspect, the present invention provides a presence of said nucleotide variant would indicate that the method for identifying high-risk patients who have a poor patient is likely to respond to an anti-tumor agent. Thus, if prognosis of a neurodegenerative or neurological disease, or the DNAJD1 gene of the patient’s tumor contains one or for the prognosis of neurodegenerative or neurological dis more of the nucleotide variants of the present invention, then ease, or predicting/determining the ability to recover from physicians may decide, based on the tumor genotyping neuronal damage resulting from brain trauma. The indi result, whether it would be desirable to treat the patient with vidual to be tested can be a healthy person or an individual US 2007/0O82347 A1 Apr. 12, 2007

diagnosed with a neurodegenerative disease, or Suffering disease, coronary artery disease, heart attack, stroke, and from Alzheimer's disease, Parkinson's disease, Hunting intestinal ischemia. If an individual is heterozygous, then his ton's disease, prion disorders, CJD. DRPLA, SCA1, SCA3, or her risk of developing ischemia or ischemic-type injury is Schizophrenia and depression. The method comprises the at an intermediate level. On the other hand, if the individual step of genotyping the individual to determine the individu is homozygous with the DNAJD1 genotype EX1(a)368C/C, als genotype at one or more of the DNAJD1 loci identified EX1(a)527A/A or EX5(a)+72w/w, then it can be reasonably in the present invention, namely SNPs EX1(a)368C, predicted that the individual has a reduced susceptibility to EX1(a)527A or EX5(a)+72w, or another locus at which the ischemia or ischemic-type injury, particularly cardiomyopa genotype is in linkage disequilibrium with one of the SNPs thy, coronary disease, coronary artery disease, heart attack, of the present invention. Thus, if one or more of the stroke, and intestinal ischemia. DNAJD1 SNPs EX1(a)368C, EX1(a)527A or EX5(a)+72w are detected, or a SNP that is in linkage disequilibrium with 0555. The SNPs on Chromosome XIII at positions any one of such SNPs is detected in the individual, then it 42,536,771, 42,554,443, 42,554,646, and 42,554,817 have can be reasonably predicted that the individual has a also been shown to be associated with DNAJD1 mRNA decreased likelihood of neurological or neurodegenerative levels. The Chromosome XIII SNPs associated with lower disease, especially Alzheimer's disease, Parkinson's dis DNAJD1 mRNA expression levels are 42,536,771T, 42.554, ease, Huntington's disease, prion disorders, CJD. DRPLA, 443A, 42.554,646A, and 42.554,817T, whereas that associ SCA1, SCA3, schizophrenia and depression, or the indi ated with higher mRNA expression levels are 42,536,771C, vidual will have a reasonable recovery from neuronal dam 42,554,443C, 42,554,646G, and 42,554,817C. In addition to age resulting from brain trauma. Alternatively, if an indi those mentioned above, these SNPs may be utilized in the vidual is homozygous with the DNAJD1 genotype applications described above. EX1(a)368T/T, EX1(a)527G/G or EX5(a)+72m/m, then the GOLPH4 individual can reasonably be assumed to have a particular poor prognosis of neurodegenerative disease, or a protracted 0556). As indicated in Tables 17, 18, 58 and 59, the or incomplete recovery from neuronal damage resulting expression level of the GOLPH4 gene in human cells is an from brain trauma. In other words, the individual has a inheritable “quantitative trait” with genetic determinants. substantially increased likelihood of or is at a substantially Furthermore, the SNPs in accordance with the present increased risk of progression of the neurodegenerative dis invention are associated with the "quantitative trait”, i.e., ease or neurological damage. However, if an individual is GOLPH4 mRNA levels in human cells. Specifically, the heterozygous with the DNAJD1 genotype EX1(a)368T/C, SNPs EX12(a)-78C, EX15(a)-85C, EX15(a)+86C, EX1(a)527G/A or EX5(a)+72m/w, an intermediate level of EX16(a)323G, EX16(a)737A, EX16(a)771G are associated risk of neurological disease, especially neurodegeneration, with a “low expression phenotype' while the EX12(a)-78T, Alzheimer's disease, Parkinson's disease, Huntington's dis EX51-85G, EX15(a)+86G, EX16(a)323A, EX16(a)737G, ease, prion disorders, CJD. DRPLA, SCA1, SCA3, schizo EX16(a)771A are associated with a “high expression phe phrenia and depression. That is, the risk is higher than a notype.” Thus, the SNPs are particularly useful in predicting person having a homozygous DNAJD1 genotype of the level of GOLPH4 gene expression in an individual. EX1(a)368C/C, EX1(a)527A/A or EX5(a)+72w/w, but is 0557 Thus, in one aspect, the present invention encom lower than a person having a homozygous genotype of passes a method for predicting or detecting an individuals EX1(a)368T/T, EX1(a)527G/G or EX5(a)+72m/m. Alterna Susceptibility to bacterial toxins, which comprises the step tively, if the individual is homozygous with the DNAJD1 of genotyping the individual to determine the individuals genotype EX1(a)368C/C, EX1(a).527A/A or EX5(a)+72w/w, genotype at one or more of the GOLPH4 loci identified in then it can be reasonably predicted that the individual does the present invention, namely, EX12(a)-78, EX15(a)-85, not have an increased likelihood or increased risk of neu EX 15(a)+86, EX16(a)323, EX16(a)737, EX16(a)771, or rodegenerative disease or neurological disease. another locus at which the genotype is in linkage disequi 0554. In yet another aspect, the present invention encom librium with one of these SNPs. Thus, if one or more passes a method for predicting or detecting ischemic or EX 12(a)-78T, EX15(a)-85G, EX15(a)+86G, EX16(a)323A, ischemic-type injury in an individual, which comprises the EX16(a)737G, EX16(a)771A, or a SNP that is in linkage step of genotyping the individual to determine the individu disequilibrium with any one of such SNPs, is detected in the als genotype at one or more of the DNAJD1 loci identified individual, then it can be reasonably predicted that the in the present invention, namely EX1(a)368, EX1(a).527 or individual is at an increased risk of developing an adverse EX5(a)+72, or another locus at which the genotype is in condition caused by bacterial toxins, particularly the ricin, linkage disequilibrium with one of these SNPs. Thus, if one cholera or Shiga toxins. or more the DNAJD1 SNPs EX1(a)368T, EX1(a)527G or 0558. In particular, if an individual is homozygous with EX5(a)+72m are detected, or a SNP that is in linkage the GOLPH4 genotype EX 12(a)-78T/T, EX15(a)-85G/G, disequilibrium with any one of such SNPs is detected in the EX 15(a)+86G/G, EX16(a)323A/A, EX16(a)737G/G, individual, it can be reasonably predicted that the individual EX16(a)771A/A, or heterozygous with the GOLPH4 geno is at an increased risk of ischemic or ischemic-type injury, type EX12(a)-78C/T, EX15(a)-85C/G, EX15(a)+86C/G, particularly cardiomyopathy, coronary disease, coronary EX16(a)323G/A, EX16(a)737A/G or EX16(a)771G/A, then artery disease, heart attack, stroke, and intestinal ischemia. it can be reasonably predicted that the individual has an In particular, if an individual is homozygous with the elevated susceptibility to bacterial toxins. In other words, DNAJD1 genotype EX1(a)368T/T, EX1(a).527G/G or Such an individual has an increased likelihood or is at an EX5(a)+72m/m, then it can be reasonably predicted that the increased risk of developing an adverse condition caused by individual has an elevated susceptibility to ischemia or bacterial toxins, particularly ricin, cholera or Shiga toxins. If ischemic-type injury, particularly cardiomyopathy, coronary an individual is homozygous with the GOLPH4 genotype US 2007/0O82347 A1 Apr. 12, 2007 64

EX 12(a)-78C/C, EX 15(a)-85C/C, EX 15(a)+86C/C, EX16(a)-42T, EX17(a) 15G, EX17(a)36C, EX17 (a87A, EX16(a)323G/G, EX16(a)737A/A or EX16(a)771G/G, then it EX18(a)903m, EX18(a) 1621A, EX18(a) 1676G, can be reasonably predicted that the individual has a reduced EX18(a) 1689m, EX(a1806T, EX18(a)2363G, Susceptibility to bacterial toxins, particularly ricin, cholera EX18(a)2373m, EX18(a)2397C, EX18(a)2586C and or Shiga toxins. EX18(a)2631A are associated with a “high expression phe notype.” Thus, the SNPs and/or haplotypes are particularly 0559). In another aspect, the present invention provides a useful in predicting the level of RABEP1 gene expression in method for identifying high-risk patients who have a poor an individual. prognosis of adverse conditions caused by bacterial toxins, or for the prognosis of a condition associated with bacterial 0562. Thus, in one aspect, the present invention encom toxins, or predicting/determining the invasiveness of bacte passes a method for predicting or detecting cancer Suscep rial toxins in a patient, particularly a patient with an adverse tibility in an individual, which comprises the step of geno condition caused by ricin, cholera, or Shiga toxin. The typing the individual to determine the individual’s genotype individual to be tested can be a healthy person or an at one or more of the RABEP1 loci identified in the present individual diagnosed with a condition caused by a bacterial invention, namely EX1(a)-551, EX1(a)73, EX18(a)276, toxin. The method comprises the step of genotyping the EX 14(a)30, EX18(a) 1782, EX18(a)646, EX18(a)690, individual to determine the individual’s genotype at one or EX16(a)-42, EX17(a)15, EX17(a)36, EX17(a)87, more of the GOLPH4 loci identified in the present invention, EX18(a)903, EX18(a) 1621, EX18(a) 1676, EX18(a) 1689, namely EX12(a)-78, EX15(a)-85, EX15(a)+86, EX16(a)323, EX(a1806, EX18(a)2363, EX18(a)2373, EX18(a)2397, EX16(a)737, EX16(a)771, or another locus at which the EX18(a).2586T and EX18(a)2631, or another locus at which genotype is in linkage disequilibrium with one of these the genotype is in linkage disequilibrium with one of the SNPs. Thus, if one or more the SNPs EX12(a)-78T, SNPs or haplotypes of the present invention. Thus, if one or EX 15(a)-85G, EX15(a)+86G, EX16(a)323A, EX16(a)737G, more the SNPs EX1(a)-551T, EX1(a)73C, EX18(a)276C, EX16(a)771A are detected, or a SNP that is in linkage EX 14(a)30C, EX18(a) 1782T, EX18(a)646w, EX18(a)690m, disequilibrium with any one of such SNPs is detected in the EX16(a)-42T, EX17(a) 15G, EX17(a)36C, EX17 (a87A, individual, then it can be reasonably predicted that the EX18(a)903m, EX18(a) 1621A, EX18(a) 1676G, individual has high invasive potential and that the condition EX18(a) 1689m, EX(a1806T, EX18(a)2363G, caused by bacterial toxins has poor prognosis. If the indi EX18(a)2373m, EX18(a)2397C, EX18(a)2586C and vidual is homozygous with the GOLPH4 genotype EX12(a)- EX18(a)2631A are detected, or a SNP that is in linkage 78T/T, EX15(a)-85G/G, EX15(a)+86G/G, EX16(a)323AJA, disequilibrium with any one of such SNPs is detected in the EX16(a)737G/G, EX16(a)771A/A, it can be reasonably pre individual, then it can be reasonably predicted that the dicted that the individual will have a particularly poor individual is at an increased risk of developing cancer. In prognosis for bacterial infection. On the other hand, if the particularly, if an individual is homozygous with the individual is homozygous with the GOLPH4 genotype RABEP1 genotype EX1(a)-551T/T, EX1(a)73C/C, EX 12(a)-78C/C, EX 15(a)-85C/C, EX 15(a)+86C/C, EX18(a)276C/C, EX14(a)30C/C, EX18(a) 1782T/T, EX16(a)323G/G, EX16(a)737A/A, EX16(a)771G/G, it can EX18(a)646w/w, EX18(a)690m/m, EX16(a)-42T/T, be reasonably predicted that the individual has an good EX17(a)15G/G, EX17(a)36C/C, EX17(a)87A/A, prognosis for bacterial infection, especially those associated EX18(a)903m/m, EX18(a) 1621A/A, EX18(a) 1676G/G, with ricin, cholera, or Shiga toxin expression. EX18(a) 1689m/m, EX(a) 1806T/T, EX18(a)2363G/G, EX18(a)2373m/m, EX18(a)2397C/C, EX18(a)2586C/C and 0560. The SNPs listed in Table 18, i.e. those at positions EX18(a)2631A/A, then it can be reasonably predicted that 169,127,554, 169,140,725, 168,943,494 and 169,109,449 of the individual has an elevated susceptibility to cancer. Like chromosome III, have also been shown to be associated with wise, if the individual is homozygous with a genotype at a GOLPH4 mRNA levels. Chromosome SNPs associated with locus that is in the same haplotype with the RABEP1 SNPs lower GOLPH4 mRNA expression levels are, whereas those EX14(a)3OT EX18(a) 1782A (in linkage disequilibrium), or associated with lower GOLPH4 mRNA expression are. In in the same haplotype (linkage disequilibrium) with the addition to those mentioned above, these SNPs may be RABEP1 SNPs EX16(a)-42A, EX17(a) 15A, EX17(a)36T, utilized in the applications described above. EX17(a)87G, EX18(a)903w, EX18(a) 1621G, EX18(a) 1676A, RABEP1 EX18(a) 1689w, EX(a1806C, EX18(a)2363A, EX18(a)2373w, EX18(a)2397G, EX18(a)2586T and 0561. As indicated in Tables 19-23 and 60-65, the expres EX18(a)2631G, or in the same haplotype (linkage disequi sion level of the RABEP1 gene in human cells is an librium) with the SNPs EX18(a)646m, EX18(a)690w, then it inheritable “quantitative trait” with genetic determinants. can reasonably be predicted that the individual has an Furthermore, the SNPs and/or haplotypes in accordance elevated Susceptibility to cancer. In other words, such an with the present invention are associated with the "quanti individual has an increased likelihood or is at an increased tative trait”, i.e., the RABEP1 mRNA level in human cells. risk of developing cancer. If an individual is heterozygous, Specifically, the SNPs EX1(a)-551C, EX1(a)73T, then his or her risk of developing cancer is at an intermediate EX18(a)276T, EX14(a)30T, EX18(a)1782A, EX18(a)646m, level. On the other hand, if the individual is homozygous EX18(a)690w, EX16(a)-42A, EX17(a)15A, EX17(a)36T, with the RABEP1 genotype EX1(a)-551C/C, EX1(a)73T/T, EX17(a)87G, EX18(a)903w, EX18(a) 1621G, EX18(a) 1676A, EX18(a)276T/T, EX 14(a)30T/T, EX18(a) 1782A/A, EX18(a) 1689w, EX(a) 1806C, EX18(a)2363A, EX18(a)646m/m, EX18(a)690w/w, EX16(a)-42A/A, EX18(a)2373w, EX18(a)2397G, EX18(a)2586T and EX17(a)15A/A, EX17(a)36T/T, EX17(a)87G/G, EX18(a)2631G are associated with a “low expression phe EX18(a)903w/w, EX18(a) 1621G/G, EX18(a) 1676A/A, notype' while the EX1(a)-551T, EX1(a)73C, EX18(a)276C, EX18(a) 1689w/w, EX(a) 1806C/C, EX18(a)2363A/A, EX 14(a)30C, EX18(a) 1782T, EX18(a)646w, EX18(a)690m, EX18(a)2373 w/w, EX18(a)2397G/G, EX18(a).2586T/T and US 2007/0O82347 A1 Apr. 12, 2007

EX18(a)2631G/G, then it can be reasonably predicted that has an intermediate prognosis, and the cells of their tumor the individual has a reduced susceptibility to cancer. Simi are potentially invasive. Specifically, the individual has an larly, if the individual is homozygous with a genotype at a intermediate level of risk for cancer metastasis. That is, the locus that is in the same haplotype with the SNPs risk is higher than a person having a homozygous RABEP1 EX14(a)30C, EX18(a) 1782T (in linkage disequilibrium), or genotype of EX1(a)-551C/C, EX1(a)73TT, EX18(a)276T/T, in the same haplotype (linkage disequilibrium) with the SNPs EX16(a)-42T, EX17(a)15G, EX17(a)36c, EX17(a)87A, EX18(a)903m, EX18(a) 1621A, EX18(a) 1676G, EX18(a) 1689m, EX(a) 1806T, EX18(a) 1621G/G, EX18(a) 1676A/A, EX18(a) 1689w/w, EX18(a)2363G, EX 18(a)2373m, EX18(a)2397C, EX18(a) 1806C/C, EX18(a)2363A/A, EX18(a)2373 w/w, EX18(a).2586C and EX18(a)2631A or in the same haplotype EX18(a)2397G/G, EX18(a)2586T/T and EX18(a)2631G/G, (linkage disequilibrium) with the SNPs EX18(a)646w, but is lower than a person having a homozygous RABEP1 EX18(a)690m, then it can reasonably be predicted that the genotype of EX1(a)-551T/T, EX1(a)73C/C, EX18(a)276C/ individual has a reduced Susceptibility to cancer. C, EX14(a)30C/C, EX18(a) 1782T/T, EX18(a)646w/w, 0563. In another aspect, the present invention provides a EX18(a)690m/m, EX16(a)-42T/T, EX17(a)15G/G, method for identifying high-risk patients who have a poor EX17(a)36C/C, EX17(a)87A/A, EX18(a)903m/m, prognosis of cancer, or for the prognosis of cancer, or EX18(a) 1621A/A, EX18(a) 1676G/G, EX18(a) 1689m/m, predicting/determining the invasiveness and metastatic EX18(a) 1806T/T, EX18(a)2363G/G, EX18(a)2373m/m, potential of a tumor in a patient. The individual to be tested EX18(a)2397C/C, EX18(a).2586C/C and EX18(a)2631A/A. can be a healthy person oran individual diagnosed of cancer. 0564) Further, if the individual is homozygous with the The method comprises the step of genotyping the individual RABEP1 genotype EX1(a)-551C/C, EX1(a)73T/T, to determine the individual’s genotype at one or more of the EX18(a)276T/T, EX14(a)30T/T, EX18(a) 1782A/A, loci identified in the present invention, namely RABEP1 EX18(a)646m/m, EX18(a)690w/w, EX16(a)-42A/A, SNPs EX1(a)-551, EX1(a)73, EX18(a)276, EX14(a)30, EX17(a)15A/A, EX17(a)36T/T, EX17(a)87G/G, EX18(a) 1782, EX18(a)646, EX18(a)690, EX16(a)-42, EX18(a)903w/w, EX18(a) 1621G/G, EX18(a) 1676A/A, EX17(a)15, EX17(a)36, EX17(a)87, EX18(a)903, EX18(a) 1689w/w, EX18(a) 1806C/C, EX18(a)2363A/A, EX18(a) 1621, EX18(a) 1676, EX18(a) 1689, EX(a1806, EX18(a)2373 w/w, EX18(a)2397G/G, EX18(a).2586T/T and EX18(a)2363, EX18(a)2373, EX18(a)2397, EX18(a)2586T EX18(a)2631G/G, then it can be reasonably predicted that and EX18(a)2631, or another locus at which the genotype is the tumor in the individual has low metastatic potential, that in linkage disequilibrium with one of these SNPs. Thus, if patient with the cancer has a good prognosis, and that the one or more the RABEP1 SNPs EX1(a)-551T, EX1(a)73C, tumor cells are likely not invasive. That is, the individual EX18(a)276C, EX14(a)30C, EX18(a) 1782T, EX18(a)646w, does not have an increased likelihood, or increased risk, for EX18(a)690m, EX16(a)-42T, EX17(a)15G, EX17(a)36C, cancer metastasis. EX17(a)87A, EX18(a)903m, EX18(a) 1621A, 0565) Another aspect of the present invention encom EX18(a) 1676G, EX18(a) 1689m, EX(a) 1806T, passes a method for predicting or detecting Susceptibility to EX18(a)2363G, EX 18(a)2373m, EX18(a)2397C, neurodegenerative disease in a patient, which comprises the EX18(a).2586C and EX18(a)2631A are detected, or a SNP step of genotyping the individual to determine the individu that is in linkage disequilibrium with any one of such SNPs als genotype at one or more of the RABEP1 loci identified is detected in the individual, then it can be reasonably in the present invention, namely EX1(a)-551, EX1(a)73, predicted that the tumor in Such an individual has high EX18(a)276, EX14(a)30, EX18(a) 1782, EX18(a)646, metastatic potential, that the cancer has poor prognosis, and EX18(a)690, EX16(a)-42, EX17(a)15, EX17(a)36, that the tumor cells are likely invasive. In other words, the EX17(a)87, EX18(a)903, EX18(a) 1621, EX18(a) 1676, individual has an increased likelihood, or is at an increased EX18(a) 1689, EX(a) 1806, EX18(a)2363, EX18(a)2373, risk for cancer metastasis. Particularly, if an individual is EX18(a)2397, EX18(a)2586T and EX18(a)2631, or another homozygous with the RABEP1 genotype EX1(a)-551T/T. locus at which the genotype is in linkage disequilibrium with EX1(a)73C/C, EX18(a)276C/C, EX 14(a)30C/C, one of the SNPs of the present invention. Thus, if one or EX18(a) 1782T/T, EX18(a)646w/w, EX18(a)690m/m, more the RABEP1 SNPs EX1(a)-551 T, EX1(a)73C, EX16(a)-42T/T, EX17(a)15G/G, EX17(a)36C/C, EX18(a)276C, EX14(a)30C, EX18(a) 1782T, EX18(a)646w, EX17(a)87A/A, EX18(a)903m/m, EX18(a) 1621A/A, EX18(a)690m, EX16(a)-42T, EX17(a) 15G, EX17(a)36C, EX18(a) 1676G/G, EX18(a) 1689m/m, EX(a) 1806T/T, EX17(a)87A, EX18(a)903m, EX18(a) 1621A, EX18(a)2363G/G, EX18(a)2373m/m, EX18(a)2397C/C, EX18(a) 1676G, EX 18(a) 1689m, EX(a) 1806T, EX18(a).2586C/C and EX18(a)2631A/A, then the individual EX18(a)2363G, EX18(a)2373m, EX18(a)2397C, has particularly poor prognosis, and cells of their tumor are EX18(a).2586C and EX18(a)2631A are detected, or a SNP likely highly invasive. In other words, the individual has a that is in linkage disequilibrium with any one of such SNPs Substantially increased likelihood, or is at a Substantially is detected in the individual, then it can be reasonably increased risk for cancer metastasis. However, if an indi predicted that the individual has increased risk of neurode vidual is heterozygous with the RABEP1 genotype EX1(a)- generative disease, especially Parkinson's disease, Alzhe 551C/T, EX1(a)73T/C, EX18(a)276T/C, EX14(a)30T/C, imer's disease, Niemann-Pick type C disease and age EX18(a) 1782A/T, EX18(a)646m/w, EX18(a690w/m, related neurodegeneration. In particular, if an individual is EX16(a)-42A/T, EX17(a)15A/G, EX17(a)36T/C, homozygous with the genotype EX1(a)-551T/T, EX1(a)73C/ EX17(a)87G/A, EX18(a)903w/m, EX18(a) 1621G/A, C, EX18(a)276C/C, EX14(a)30C/C, EX18(a) 1782T/T, EX18(a) 1676A/G, EX18(a) 1689w/m, EX(a) 1806C/T, EX18(a)646w/w, EX18(a)690m/m, EX16(a)-42T/T, EX18(a)2363A/G, EX18(a)2373 w/m, EX18(a)2397G/C, EX17(a)15G/G, EX17(a)36C/C, EX17(a)87A/A, EX18(a).2586T/C and EX18(a)2631G/A, then the individual EX18(a)903m/m, EX18(a) 1621A/A, EX18(a) 1676G/G, US 2007/0O82347 A1 Apr. 12, 2007 66

EX18(a) 1689m/m, EX18(a) 1806T/T, EX18(a)2363G/G, an intermediate level of risk of neurological disease, espe EX18(a)2373m/m, EX18(a)2397C/C, EX18(a)2586C/C and cially Parkinson's disease, Alzheimer's disease, Niemann EX18(a)2631A/A, then it can be reasonably predicted that Pick type C disease and age-related neurodegeneration. That the individual has an elevated Susceptibility to neurodegen is, the risk is higher than a person having a homozygous erative disease. In other words, such an individual has an genotype of EX1(a)-551C/C, EX1(a)73TT, EX18(a)276T/T, increased likelihood or is at an increased risk of developing EX 14(a)30T/T, EX18(a) 1782A/A, EX18(a)646m/m, EX1 a neurodegenerative disease. If an individual is heterozy 8(a)690w/w, EX16(a)-42A/A, EX17(a)15A/A, EX17(a)36T/ gous, then his or her risk of developing Parkinson's disease, T, EX17(a)87G/G, EX18(a)903w/w, EX18(a) 1621G/G, Alzheimer's disease, Niemann-Pick type C disease and EX18(a) 1676A/A, EX18(a) 1689w/w, EX(a) 1806C/C, age-related neurodegeneration, is at an intermediate level. EX18(a)2363A/A, EX18(a)2373 w/w, EX18(a)2397G/G, On the other hand, if the individual is homozygous with the EX18(a).2586T/T and EX18(a)2631G/G, but is lower than a genotype SNPs EX1(a)-551C/C, EX1(a)73T/T, person having a homozygous genotype of EX1(a)-551 T/T. EX18(a)276T/T, EX14(a)30T/T, EX18(a) 1782A/A, EX1(a)73C/C, EX18(a)276C/C, EX 14(a)30C/C, EX18(a)646m/m, EX18(a)690w/w, EX16(a)-42A/A, EX18(a) 1782T/T, EX18(a)646w/w, EX18(a)690m/m, EX17(a)15A/A, EX17(a)36T/T, EX17(a)87G/G, EX16(a)-42T/T, EX17(a)15G/G, EX17(a)36C/C, EX18(a)903w/w, EX18(a) 1621G/G, EX18(a) 1676A/A, EX17(a)87A/A, EX18(a)903m/m, EX18(a) 1621A/A, EX18(a) 1689w/w, EX18(a) 1806C/C, EX18(a)2363A/A, EX18(a) 1676G/G, EX18(a) 1689m/m, EX18(a) 1806T/T, EX18(a)2373 w/w, EX18(a)2397G/G, EX18(a)2586T/T and EX18(a)2363G/G, EX18(a)2373m/m, EX18(a)2397C/C, EX18(a)2631G/G, then it can be reasonably predicted that EX18(a)2586C/C and EX18(a)2631A/A. the individual has a reduced susceptibility to neurodegen erative disease, especially Parkinson's disease, Alzheimer's 0567 The SNPs listed in Table 23, i.e. those at positions disease, Niemann-Pick type C disease and age-related neu 5,238,870, 5,264,880, 5,265,310, 5,251,617, 5,250,885 and rodegeneration. 5.255,563 of , have also been shown to be associated with RABEP1 mRNA levels. In addition to those 0566 In another aspect, the present invention provides a mentioned above, these SNPs may be utilized in the appli method for identifying high-risk patients who have a poor cations described above. prognosis of a neurodegenerative or neurological disease, or for the prognosis of neurodegenerative or neurological dis TAP2 ease, or predicting/determining the ability to recover from 0568. As indicated in Tables 24, 25 and 66-70 below, the neuronal damage resulting from brain trauma. The indi expression level of the TAP2 gene in human cells is an vidual to be tested can be a healthy person or an individual inheritable “quantitative trait” with genetic determinants. diagnosed with or neurodegenerative disease. Thus, if one or Furthermore, the SNPs and/or haplotypes in accordance more of the SNPs EX1(a)-551T, EX1(a)73C, EX18(a)276C, with the present invention are associated with the "quanti EX 14(a)30C, EX18(a) 1782T, EX18(a)646w, EX18(a)690m, tative trait”, i.e., mRNA level of the TAP2 gene in human EX16(a)-42T, EX17(a) 15G, EX17(a)36C, EX17 (a87A, cells. Specifically, the SNPs EX8(a)36C, EX10(a)+23T, EX18(a)903m, EX18(a) 1621A, EX18(a) 1676G, EX 12(a) 19C, EX12(a)61A, EX12(a)127T, EX12(a)332A, EX18(a) 1689m, EX(a1806T, EX18(a)2363G, EX 12(a)356G, EX11(a) 17A, EX11(a)+9C, EX12(a) 159G, EX18(a)2373m, EX18(a)2397C, EX18(a)2586C and EX 12(a)291G, EX12(a)358w, EX12(a)466A, EX12(a)586C, EX18(a)2631A are detected, or a SNP that is in linkage EX 12(a)668T, EX12(a)754G, EX12(a)755C, EX12(a)793G, disequilibrium with any one of such SNPs is detected in the EX12(a)847C and EX12(a)1132w are associated with a “low individual, then it can be reasonably predicted that the expression phenotype' while the EX8(a)36T, EX10(a)+23C, individual has an increased likelihood of neurodegenerative EX 12(a) 19T EX12(a)61G, EX12(a)127C, EX12(a)332G, disease, especially Parkinson's disease, Alzheimer's dis EX 12(a)356T, EX11(a)17G, EX11(a)+9T EX12(a)159T. ease, Niemann-Pick type C disease and age-related neuro EX 12(a)291A, EX12(a)358m, EX12(a)466G, EX12(a)586T, degeneration. Particularly, if an individual is homozygous EX 12(a)668C, EX12(a)754A, EX12(a)755T, EX12(a)793T, with the genotype EX1(a)-551T/T, EX1(a)73C/C, EX12(a)847T and EX12(a) 1132m are associated with a “high EX18(a)276C/C, EX 14(a)30C/C, EX18(a) 1782T/T, expression phenotype.” Thus, the SNPs and/or haplotypes EX18(a)646w/w, EX18(a)690m/m, EX16(a)-42T/T, are particularly useful in predicting the level of TAP2 gene EX17(a)15G/G, EX17(a)36C/C, EX17(a)87A/A, expression in an individual. EX18(a)903m/m, EX18(a) 1621A/A, EX18(a) 1676G/G, EX18(a) 1689m/m, EX18(a) 1806T/T, EX18(a)2363G/G, 0569. Thus, in one aspect, the present invention encom EX18(a)2373m/m, EX18(a)2397C/C, EX18(a)2586C/C and passes a method for predicting or detecting cancer Suscep EX18(a)2631A/A, then the individual has particular poor tibility in an individual, which comprises the step of geno prognosis neurodegenerative disease or damage will have typing the individual to determine the individual’s genotype greater effects. In other words, the individual has a substan at one or more of the TAP2 loci identified in the present tially increased likelihood or at a substantially increased risk invention, namely EX8(a)36, EX10(a)+23, EX12(a) 19, of progression of the neurodegenerative disease or damage. EX 12(a)61, EX12(a)127, EX12(a)332, EX12(a)356, However, if an individual is heterozygous with the genotype EX 11(a) 17, EX1(a)1B+9, EX12(a) 159G, EX12(a)291, EX1(a)-551C/T, EX1(a)73T/C, EX18(a)276T/C, EX 12(a)358, EX12(a)466, EX12(a)586, EX12(a)668, EX 14(a)30T/C, EX18(a) 1782A/T, EX18(a)646m/w, EX 12(a)754, EX12(a)755, EX12(a)793, EX12(a)847 or EX18(a)690w/m, EX16(a)-42A/T, EX17(a)15A/G, EX12(a) 1132, or another locus at which the genotype is in EX17(a)36T/C, EX17(a)87G/A, EX18(a)903w/m, linkage disequilibrium with one of the SNPs or haplotypes EX18(a) 1621G/A, EX18(a) 1676A/G, EX18(a) 1689w/m, of the present invention. Thus, if one or more the EX(a1806C/T, EX18(a)2363A/G, EX18(a)2373w/m, EX8(a)36C, EX10(a)+23T, EX12(a) 19C, EX12(a)61A, EX18(a)2397G/C, EX18(a)2586T/C and EX18(a)2631G/A, EX 12(a)127T, EX12(a)332A, EX12(a)356G, EX11(a)17A, US 2007/0O82347 A1 Apr. 12, 2007 67

EX 11(a)+9C, EX12(a)159G, EX12(a)291G, EX12(a)358w, itself, by determining the nucleotide present at one or more EX 12(a)466A, EX12(a)586C, EX12(a)668T, EX12(a)754G, of the TAP2 loci identified in the present invention, namely EX12(a)755C, EX 12(a)793G, EX 12(a)847C O EX8(a)36, EX10(a)+23, EX12(a) 19, EX12(a)61, EX12(a) 127, EX12(a) 1132w are detected, or a SNP that is in linkage EX 12(a)332, EX12(a)356, EX11(a) 17, EX11(a)+9, disequilibrium with any one of such SNPs is detected in the EX 12(a)159G, EX12(a).291, EX12(a)358, EX12(a)466, individual, then it can be reasonably predicted that the EX 12(a)586, EX12(a)668, EX12(a)754, EX12(a)755, individual is at an increased risk of developing cancer, EX12(a)793, EX12(a)847 or EX12(a)1132, or another locus particularly skin cancer, breast cancer or Small cell lung at which the genotype is in linkage disequilibrium with one cancer. In particularly, if an individual is homozygous with of the SNPs or haplotypes of the present invention. Thus, if the TAP2 genotype EX8(a)36C/C, EX10(a)+23T/T, EX 12(a) 19C/C, EX12(a)61A/A, EX12(a)127T/T, one or more the TAP2 SNPs EX8(a)36C, EX10(a)+23T, EX 12(a)332A/A, EX 12(a)356G/G, EX 11(a)17A/A, EX 12(a) 19C, EX12(a)61A, EX12(a)127T, EX12(a)332A, EX 11(a)+9C/C, EX 12(a)159G/G, EX 12(a)291G/G, EX 12(a)356G, EX11(a) 17A, EX11(a)+9C, EX12(a) 159G, EX 12(a)358w/w, EX12(a)466A/A, EX 12(a)586C/C, EX 12(a)291G, EX12(a)358w, EX12(a)466A, EX12(a)586C, EX 12(a)668T/T, EX 12(a)754G/G, EX12(a)755C/C, EX 12(a)668T, EX12(a)754G, EX12(a)755C, EX12(a)793G, EX 12(a)793G/G, EX12(a)847C/C or EX12(a)1132w/w, then EX12(a)847C or EX12(a)1132w are detected, or a SNP that it can be reasonably predicted that the individual has an is in linkage disequilibrium with any one of such SNPs is elevated Susceptibility to cancer, particularly skin cancer, detected in the cancerous growth or tumor, then it can be breast cancer or Small cell lung cancer. Likewise, if the reasonably predicted that the cancerous growth or tumor has individual is homozygous with a genotype at a TAP2 locus high metastatic potential, that the cancer has poor prognosis, that is in the same haplotype with the SNPs EX12(a)61A, and that the cells of the cancerous growth or tumor are likely EX 12(a)127T, EX12(a)332A, EX12(a)356G, EX11(a)17A, invasive. In other words, the patient with a cancerous growth EX 11(a)+9C, EX12(a)159G, EX12(a)291G, EX12(a)358w, or tumor with Such a genotype has an increased likelihood, EX 12(a)466A, EX12(a)586C, EX12(a)668T, EX12(a)754G, or increased risk, of metastatic cancer. Particularly, if the EX12(a)755C, EX 12(a)793G, EX 12(a)847C O cancerous growth or tumor is homozygous with the TAP2 EX12(a) 1132w (in linkage disequilibrium), then it can rea genotype EX8(a)36C/C, EX10(a)+23T/T, EX12(a)19C/C, sonably be predicted that the individual has an elevated EX12(a)61A/A, EX12(a)127T/T, EX 12(a)332A/A, Susceptibility to cancer, particularly skin cancer, breast EX 12(a)356G/G, EX 11(a)17A/A, EX 11(a)+9C/C, cancer or Small cell lung cancer. In other words, such an EX 12(a)159G/G, EX 12(a)291G/G, EX 12(a)358w/w, individual has an increased likelihood or is at an increased EX12(a)466AJA, EX12(a)586C/C, EX12(a)668T/T, risk of developing cancer, particularly skin cancer, breast EX 12(a)754G/G, EX12(a)755C/C, EX 12(a)793G/G, cancer or Small cell lung cancer. If an individual is heterozy EX12(a)847C/C or EX12(a)1132w/w, then the patient has gous, then his or her risk of developing cancer is at an particularly poor prognosis and their tumor cells are likely intermediate level. On the other hand, if the individual is highly invasive capable of rapid growth. In other words, the homozygous with the TAP2 genotype EX8(a)36T/T. individual has a substantially increased likelihood or at a EX 10(a)+23C/C, EX12(a)19T/T, EX 12(a)61G/G, Substantially increased risk of cancer metastasis and rapid EX 12(a)127C/C, EX 12(a)332G/G, EX12(a)356T/T, cancer growth. However, if the cancerous growth or tumor EX 11(a)17G/G, EX1 1(a)+9T/T, EX12(a)159T/T, is heterozygous with the TAP2 genotype EX8(a)36C/T. EX12(a).291A/A, EX12(a)358m/m, EX12(a)466G/G, EX 10(a)+23T/C, EX 12(a) 19C/T, EX12(a)61A/G, EX12(a)586T/T, EX 12(a)668C/C, EX 12(a)754A/A, EX12(a)127T/C, EX 12(a)332A/G, EX 12(a)356G/T, EX12(a)755T/T, EX12(a)793T/T, EX12(a)847T/T or EX 11(a)17A/G, EX 11(a)+9C/T, EX12(a)159G/T, EX12(a) 1132m/m, then it can be reasonably predicted that EX 12(a)291G/A, EX12(a)358w/m, EX12(a)466A/G, the individual has a reduced Susceptibility to cancer, par EX12(a)586C/T, EX 12(a)668T/C, EX 12(a)754G/A, ticularly skin cancer, breast cancer or Small cell lung cancer. EX12(a)755C/T, EX12(a)793G/T, EX12(a847C/T or Similarly, if the individual is homozygous with a genotype EX12(a) 1132w/m, then the patient has a somewhat less poor at a TAP2 locus that is in the same haplotype with the SNPs prognosis and their tumor cells are likely only moderately EX 12(a)61G, EX12(a)127C, EX12(a)332G, EX12(a)356T, invasive. Specifically, the patient has an intermediate level EX 11(a)17G, EX11(a)+9T EX12(a)159T, EX12(a)291A, of risk of cancer metastasis. That is, the risk is greater than EX 12(a)358m, EX12(a)466G, EX12(a)586T, EX12(a)668C, a patient having a cancerous growth or tumor that has a EX12(a)754A, EX12(a)755T, EX12(a)793T, EX12(a)847T homozygous TAP2 genotype of EX8(a)36C/C, EX10(a)+ and EX12(a) 1132m (in linkage disequilibrium), then it can 23T/T, EX12(a) 19C/C, EX12(a)61A/A, EX12(a)127T/T, reasonably be predicted that the individual has a reduced EX 12(a)332A/A, EX 12(a)356G/G, EX 11(a)17A/A, Susceptibility to cancer, particularly skin cancer, breast EX 11(a)+9C/C, EX 12(a)159G/G, EX 12(a)291G/G, cancer or Small cell lung cancer. EX 12(a)358w/w, EX12(a)466A/A, EX 12(a)586C/C, EX 12(a)668T/T, EX 12(a)754G/G, EX12(a)755C/C, 0570. In another aspect, the present invention provides a EX 12(a)793G/G, EX12(a)847C/C or EX12(a)1132w/w, but is method for identifying patients who's cancer has a poor lower than a patient having a cancerous growth or tumor that prognosis, or for predicting or determining the potential has a homozygous TAP2 genotype of EX8(a)36T/T. invasiveness and metastatic potential of tumor in a patient, EX 10(a)+23C/C, EX12(a)19T/T, EX 12(a)61G/G, particularly cancer patient, e.g., with cancer Such as mela EX 12(a)127C/C, EX 12(a)332G/G, EX12(a)356T/T, noma, breast cancer or Small cell lung cancer. The patient to EX 11(a)17G/G, EX 11(a)+9T/T, EX12(a)159T/T, be tested can be a patient diagnosed with cancer, particularly EX12(a).291A/A, EX12(a)358m/m, EX12(a)466G/G, melanoma, breast cancer or Small cell lung cancer. The EX12(a)586T/T, EX 12(a)668C/C, EX 12(a)754A/A, method comprises the steps of genotyping the cancerous EX12(a)755T/T, EX12(a)793T/T, EX12(a)847T/T or growth, or tumor, to determine the genotype of the cancer EX12(a) 1132m/m. US 2007/0O82347 A1 Apr. 12, 2007

0571 Thus, if the patient has a cancerous growth or EX 12(a)127T, EX12(a)332A, EX12(a)356G, EX11(a)17A, tumor that has a homozygous TAP2 genotype of EX8(a)36T/ EX 11(a)+9C, EX12(a) 159G, EX12(a)291G, EX12(a)358w, T, EX10(a)+23C/C, EX12(a) 19T/T, EX12(a)61G/G, EX 12(a)466A, EX12(a)586C, EX12(a)668T, EX12(a)754G, EX 12(a)127C/C, EX12(a)332G/G, EX12(a)356T/T, EX12(a)755C, EX 12(a)793G, EX 12(a)847C O EX 11(a)17G/G, EX 11(a)+9T/T, EX 12(a)159T/T, EX12(a) 1132w (in linkage disequilibrium), then it can rea EX12(a).291A/A, EX12(a)358m/m, EX12(a)466G/G, sonably be predicted that the individual has an elevated EX 12(a)586T/T, EX12(a)668C/C, EX12(a)754A/A, Susceptibility to autoimmune disease, particularly Wegen EX12(a)755T/T, EX12(a)793T/T, EX12(a)847T/T or er's granulomatosis, multiple Sclerosis, type 1 diabetes mel EX12(a) 1132m/m, then it can be reasonably predicted that litus, lupus, and rheumatoid arthritis. In other words, such an the tumor in the individual has low metastic potential, that individual has an increased likelihood or is at an increased the cancer has a better prognosis, and that the tumor cells are risk of developing autoimmune disease, particularly Wege likely less invasive and give to rapid growth. That is, the ner's granulomatosis, multiple Sclerosis, type 1 diabetes patient does not have an increased likelihood or increased mellitus, lupus, and rheumatoid arthritis. If an individual is risk of cancer metastasis. Similarly, if the cancerous growth heterozygous, then his or her risk of developing autoimmune or tumor is homozygous with a genotype at a TAP2 locus disease is at an intermediate level. One the other hand, if the that is in the same haplotype with the SNPs EX12(a)61G/G, individual is homozygous with the TAP2 genotype EX 12(a)127C/C, EX 12(a)332G/G, EX12(a)356T/T, EX8(a)36T/T, EX10(a)+23C/C, EX12(a)19T/T, EX12(a)61G/ EX 11(a)17G/G, EX 11(a)+9T/T, EX 12(a)159T/T, G, EX12(a)127C/C, EX12(a)332G/G, EX12(a)356T/T, EX12(a).291A/A, EX12(a)358m/m, EX12(a)466G/G, EX 11(a)17G/G, EX 11(a)+9T/T, EX12(a)159T/T, EX12(a)586T/T, EX 12(a)668C/C, EX 12(a)754A/A, EX12(a).291A/A, EX12(a)358m/m, EX12(a)466G/G, EX12(a)755T/T, EX12(a)793T/T, EX12(a)847T/T or EX12(a)586T/T, EX 12(a)668C/C, EX 12(a)754A/A, EX12(a) 1132m/m (in linkage disequilibrium), then it can EX12(a)755T/T, EX12(a)793T/T, EX12(a)847T/T or reasonably be predicted that the cancer has a low metastatic EX12(a) 1132m/m, then it can be reasonably predicted that potential, has good prognosis, and the tumor cells are likely the individual has a reduced Susceptibility to autoimmune less invasive. In other words, the patient does not have an disease, particularly Wegener's granulomatosis, multiple increased likelihood or increased risk of cancer metastasis. Sclerosis, type 1 diabetes mellitus, lupus, and rheumatoid arthritis. Similarly, if the individual is homozygous with a 0572 In another aspect, the present invention encom genotype at a locus that is in the same haplotype with the passes a method for predicting or detecting Susceptibility to TAP2 SNPs EX12(a)61G, EX12(a)127C, EX12(a)332G, autoimmune disease in an individual, which comprises the EX 12(a)356T, EX11(a)17G, EX11(a)+9T EX12(a)159T. step of genotyping the individual to determine the individu EX 12(a)291A, EX12(a)358m, EX12(a)466G, EX12(a)586T, als genotype at one or more of the TAP2 loci identified in EX 12(a)668C, EX12(a)754A, EX12(a)755T, EX12(a)793T, the present invention, namely EX8(a)36, EX10(a)+23, EX12(a)847T and EX12(a) 1132m (in linkage disequilib EX 12(a) 19, EX12(a)61, EX12(a)127, EX12(a)332, rium), then it can reasonably be predicted that the individual EX 12(a)356, EX11(a) 17, EX11(a)+9, EX12(a) 159G, has a reduced susceptibility to autoimmune disease, particu EX 12(a)291, EX12(a)358, EX12(a)466, EX12(a)586, larly Wegener's granulomatosis, multiple Sclerosis, type 1 EX 12(a)668, EX12(a)754, EX12(a)755, EX12(a)793, diabetes, lupus, mellitus and rheumatoid arthritis. EX12(a)847 or EX12(a)1132, or another locus at which the genotype is in linkage disequilibrium with one of the SNPs 0573. In yet another aspect, the present invention encom or haplotypes of the present invention. Thus, if one or more passes a method for predicting or detecting Susceptibility to the TAP2 SNPs EX8(a)36C, EX10(a)+23T, EX12(a) 19C, viral infection in an individual, which comprises the step of EX 12(a)61A, EX12(a)127T, EX12(a)332A, EX12(a)356G, genotyping the individual to determine the individuals EX 11(a) 17A, EX1(a)+9C, EX12(a) 159G, EX12(a)291G, genotype at one or more of the TAP2 loci identified in the EX 12(a)358w, EX12(a)466A, EX12(a)586C, EX12(a)668T, present invention, namely EX8(a)36, EX10(a)+23, EX12(a)754G, EX12(a)755C, EX12(a)793G, EX12(a847C EX 12(a) 19, EX12(a)61, EX12(a)127, EX12(a)332, or EX12(a) 1132w are detected, or a SNP that is in linkage EX 12(a)356, EX11(a) 17, EX11(a)+9, EX12(a) 159G, disequilibrium with any one of such SNPs is detected in the EX 12(a)291, EX12(a)358, EX12(a)466, EX12(a)586, individual, then it can be reasonably predicted that the EX 12(a)668, EX12(a)754, EX12(a)755, EX12(a)793, individual is at an increased risk of developing an autoim EX12(a)847 or EX12(a)1132, or another locus at which the mune disease, particularly Wegener's granulomatosis, mul genotype is in linkage disequilibrium with one of the SNPs tiple Sclerosis, type 1 diabetes mellitus, lupus, and rheuma or haplotypes of the present invention. Thus, if one or more toid arthritis. In particularly, if an individual is homozygous the TAP2 SNPs EX8(a)36C, EX10(a)+23T, EX12(a) 19C, with the TAP2 genotype EX8(a)36C/C, EX10(a)+23T/T, EX 12(a)61A, EX12(a)127T, EX12(a)332A, EX12(a)356G, EX 12(a) 19C/C, EX12(a)61A/A, EX12(a)127T/T, EX 11(a) 17A, EX11(a)+9C, EX12(a)159G, EX12(a)291G, EX 12(a)332A/A, EX 12(a)356G/G, EX 11(a)17A/A, EX 12(a)358w, EX12(a)466A, EX12(a)586C, EX12(a)668T, EX 11(a)+9C/C, EX 12(a)159G/G, EX 12(a)291G/G, EX12(a)754G, EX12(a)755C, EX12(a)793G, EX12(a847C EX 12(a)358w/w, EX12(a)466A/A, EX 12(a)586C/C, or EX12(a) 1132w are detected, or a SNP that is in linkage EX 12(a)668T/T, EX 12(a)754G/G, EX12(a)755C/C, disequilibrium with any one of such SNPs is detected in the EX 12(a)793G/G, EX12(a)847C/C or EX12(a)1132w/w, then individual, then it can be reasonably predicted that the it can be reasonably predicted that the individual has an individual is at an increased risk of developing viral infec elevated Susceptibility to autoimmune disease, particularly tion. In particularly, if an individual is homozygous with the Wegener's granulomatosis, multiple Sclerosis, type 1 diabe TAP2 genotype EX8(a)36C/C, EX10(a)+23T/T, tes mellitus, lupus, and rheumatoid arthritis. Likewise, if the EX 12(a) 19C/C, EX12(a)61A/A, EX12(a)127T/T, individual is homozygous with a TAP2 genotype at a locus EX 12(a)332A/A, EX12(a)3356G/G, EX11(a) 17A/A, that is in the same haplotype with the SNPs EX12(a)61A, EX 11(a)+9C/C, EX12(a) 159G/G, EX12(a).291G/G, US 2007/0O82347 A1 Apr. 12, 2007 69

EX 12(a)358w/w, EX12(a)466A/A, EX 12(a)586C/C, T, EX12(a) 19C/C, EX12(a)61A/A, EX12(a)127T/T, EX 12(a)668T/T, EX 12(a)754G/G, EX12(a)755C/C, EX 12(a)332A/A, EX12(a)356G/G, EX11(a) 17A/A, EX 12(a)793G/G, EX12(a)847C/C or EX12(a)1132w/w, then EX 11(a)+9C/C, EX12(a) 159G/G, EX12(a).291G/G, it can be reasonably predicted that the individual has an EX 12(a)358w/w, EX12(a)466A/A, EX12(a)586C/C, elevated susceptibility to viral infection. Likewise, if the EX12(a)668T/T, EX12(a)754G/G, EX12(a)755C/C, individual is homozygous with a genotype at a TAP2 locus EX 12(a)793G/G, EX12(a)847C/C or EX12(a)1132w/w, then that is in the same haplotype with the SNPs EX12(a)61A, the individual has particularly poor viral infection prognosis. EX 12(a)127T, EX12(a)332A, EX12(a)356G, EX11(a)17A, In other words, the individual has a substantially increased EX 11(a)+9C, EX12(a)159G, EX12(a)291G, EX12(a)358w, likelihood or at a substantially increased risk of viral repli EX 12(a)466A, EX12(a)586C, EX12(a)668T, EX12(a)754G, cation. However, if an individual is heterozygous with the EX12(a)755C, EX 12(a)793G, EX 12(a)847C O TAP2 genotype EX8(a)36C/T, EX1O(a)+23T/C, EX12(a) 1132w (in linkage disequilibrium), then it can rea EX 12(a) 19C/T, EX12(a)61A/G, EX12(a)127T/C, sonably be predicted that the individual has an elevated EX 12(a)332A/G, EX12(a)356G/T, EX11(a)17A/G, EX11(a)+ susceptibility to viral infection. In other words, such an 9C/T, EX12(a) 159G/T, EX12(a).291G/A, EX12(a)358w/m, individual has an increased likelihood or is at an increased EX12(a)466A/G, EX12(a)586C/T, EX 12(a)668T/C, risk of developing viral infection. If an individual is het EX 12(a)754G/A, EX12(a)755C/T, EX12(a)793G/T, erozygous, then his or her risk of developing viral infection EX12(a)847C/T or EX12(a) 1132w/m, then the individual has is at an intermediate level. One the other hand, if the poor prognosis. Specifically, the individual has an interme individual is homozygous with the TAP2 genotype diate level of risk of progression of viral infection and/or EX8(a)36T/T, EX10(a)+23C/C, EX12(a)19T/T, EX12(a)61G/ viral replication. That is, the risk is greater than a person G, EX12(a)127C/C, EX12(a)332G/G, EX12(a)356T/T, having a homozygous TAP2 genotype of EX8(a)36C/C, EX 11(a)17G/G, EX 11(a)+9T/T, EX 12(a)159T/T, EX 10(a)+23T/T, EX 12(a)19C/C, EX12(a)61A/A, EX12(a).291A/A, EX12(a)358m/m, EX12(a)466G/G, EX12(a)127T/T, EX 12(a)332A/A, EX 12(a)356G/G, EX12(a)586T/T, EX 12(a)668C/C, EX 12(a)754A/A, EX 11(a)17A/A, EX 11(a)+9C/C, EX 12(a)159G/G, EX12(a)755T/T, EX12(a)793T/T, EX12(a)847T/T or EX 12(a)291G/G, EX 12(a)358w/w, EX12(a)466A/A, EX12(a) 1132m/m, then it can be reasonably predicted that EX 12(a)586C/C, EX 12(a)668T/T, EX 12(a)754G/G, the individual has a reduced susceptibility to viral infection. EX12(a)755C/C, EX12(a)793G/G, EX12(a)847C/C or Similarly, if the individual is homozygous with a genotype EX12(a) 1132w/w, but is lower than a person having a at a TAP2 locus that is in the same haplotype with the SNPs homozygous TAP2 genotype of EX8(a)36T/T, EX10(a)+ EX 12(a)61G, EX12(a)127C, EX12(a)332G, EX12(a)356T, 23C/C, EX12(a) 19T/T, EX12(a)61G/G, EX12(a)127C/C, EX 11(a)17G, EX11(a)+9T EX12(a)159T, EX12(a)291A, EX 12(a)332G/G, EX12(a)356T/T, EX11(a)17G/G, EX1 EX 12(a)358m, EX12(a)466G, EX12(a)586T, EX12(a)668C, 1(a)+9T/T, EX12(a) 159T/T, EX12(a)291A/A, EX12(a)358m/ EX12(a)754A, EX12(a)755T, EX12(a)793T, EX12(a)847T m, EX12(a)466G/G, EX12(a)586T/T, EX12(a)668C/C, and EX12(a) 1132m (in linkage disequilibrium), then it can EX 12(a)754A/A, EX12(a)755T/T, EX12(a)793T/T, reasonably be predicted that the individual has a reduced EX 12(a)847T/T or EX12(a)1132m/m. susceptibility to viral infection. 0575 Thus, if the individual is homozygous with the 0574. In still another aspect, the present invention pro TAP2 genotype EX8(a)36T/T, EX 10(a)+23C/C, vides a method for identifying high-risk patients who have EX12(a) 19T/T, EX 12(a)61G/G, EX 12(a)127C/C, a poor viral infection prognosis, or for the prognosis of viral EX 12(a)332G/G, EX12(a)356T/T, EX11(a) 17G/G, EX11(a)+ infection, or predicting/determining the invasiveness and 9T/T, EX12(a)159T/T, EX12(a)291A/A, EX12(a)358m/m, potential for viral replication in a patient. The individual to EX12(a)466G/G, EX12(a)586T/T, EX 12(a)668C/C, be tested can be a healthy person or an individual diagnosed EX 12(a)754A/A, EX12(a)755T/T, EX12(a)793T/T, with viral infection. The method comprises the step of EX12(a)847T/T or EX12(a)1132m/m, then it can be reason genotyping the individual to determine the individuals ably predicted that the viral infection in the individual has genotype at one or more of the TAP2 loci identified in the low replication potential, that the individual has a good present invention, namely EX8(a)36, EX10(a)+23, prognosis. That is, the individual does not have an increased EX 12(a) 19, EX12(a)61, EX12(a)127, EX12(a)332, likelihood or increased risk of viral replication and/or viral EX 12(a)356, EX11(a) 17, EX11(a)+9, EX12(a) 159G, infection progression. Similarly, if the individual is homozy EX 12(a)291, EX12(a)358, EX12(a)466, EX12(a)586, gous with a genotype at a TAP2 locus that is in the same EX 12(a)668, EX12(a)754, EX12(a)755, EX12(a)793, haplotype with the SNPs EX12(a)61G/G, EX12(a)127C/C, EX12(a)847 or EX12(a)1132, or another locus at which the EX 12(a)332G/G, EX12(a)356T/T, EX11(a) 17G/G, EX11(a)+ genotype is in linkage disequilibrium with one of the SNPs 9T/T, EX12(a)159T/T, EX12(a)291A/A, EX12(a)358m/m, or haplotypes of the present invention. Thus, if one or more EX12(a)466G/G, EX12(a)586T/T, EX 12(a)668C/C, the TAP2 SNPs EX8(a)36C, EX10(a)+23T, EX12(a) 19C, EX 12(a)754A/A, EX12(a)755T/T, EX12(a)793T/T, EX 12(a)61A, EX12(a)127T, EX12(a)332A, EX12(a)356G, EX12(a)847T/T or EX12(a)1132m/m (in linkage disequilib EX 11(a) 17A, EX11(a)+9C, EX12(a)159G, EX12(a)291G, rium), then it can reasonably be predicted that the individual EX 12(a)358w, EX12(a)466A, EX12(a)586C, EX12(a)668T, has a low replication potential, that the individual has a good EX12(a)754G, EX12(a)755C, EX12(a)793G, EX12(a847C prognosis. In other words, the individual does not have an or EX12(a) 1132w are detected, or a SNP that is in linkage increased likelihood or increased risk of viral infection disequilibrium with any one of such SNPs is detected in the progression. individual, then it can be reasonably predicted that the 0576) The SNPs listed in Table 25, i.e. those at positions individual has an increase likelihood or increased potential 32,511,862 and 32,512,605 of chromosome 6, have also of viral replication. Particularly, if an individual is homozy been shown to be associated with TAP2 mRNA levels. gous with the TAP2 genotype EX8(a)36C/C, EX1O(a)+23T/ Chromosome 6 SNPs associated with lower TAP2 mRNA US 2007/0O82347 A1 Apr. 12, 2007 70 expression levels are 32,511,862T and 32,512,605A, individual’s genotype at one or more of the loci identified in whereas those associated with lower TAP2 mRNA expres the present invention, namely EX10(a)-23, EX12(a)48, sion are 32,511,862C and 32,512,605C. In addition to those EX 14(a)+15, EX16(a) 1757, EX16(a)2306, EX16(a)2547 and mentioned above, these SNPs may be utilized in the appli EX16(a)4025, or another locus at which the genotype is in cations described above. linkage disequilibrium with one of the SNPs or haplotypes of the present invention. Thus, if one or more the SNPs NARG2 EX 10(a)-23A, EX12(a)48C, EX14(a)+15C, EX16(a) 1757m, 0577 As indicated in Tables 26, 71 and 72, the expres EX16(a)2306C, EX16(a)2547T and EX16(a)4025w are sion level of the NARG2 gene in human cells is an inher detected, or a SNP that is in linkage disequilibrium with any itable "quantitative trait” with genetic determinants. Fur one of such SNPs is detected in the individual, then it can be thermore, the SNPs in accordance with the present invention reasonably predicted that the individual is at an increased are associated with the “quantitative trait”, i.e. mRNA level risk of developing neurodegenerative disease, particularly of the NARG2 gene in human cells. Specifically, the SNPs ALS, Parkinson's disease, Alzheimer's disease and other EX 10(a)-23A, EX12(a)48C, EX14(a)+15C, EX16(a) 1757m, types of brain and spinal cord injury. In particular, if an EX16(a)2306C, EX16(a)2547T and EX16(a)4025w are asso individual is homozygous with the genotype EX10(a)-23A/ ciated with the “low expression phenotype' while the A, EX12(a)48C/C, EX14(a)+15C/C, EX16(a)1757m/m, EX 10(a)-23C, EX12(a)48T, EX14(a)+15G, EX16(a)1757w, EX16(a)2306C/C, EX16(a)2547T/T and EX16(a)4025w/w, EX16(a)2306G, EX16(a)2547G and EX16(a)4025m are asso then it can be reasonably predicted that the individual has an ciated with “high expression phenotype.” Thus, the SNPs elevated Susceptibility to neurodegenerative disease, par are particularly useful in predicting the NARG2 gene ticularly ALS, Parkinson's disease, Alzheimer's disease and expression and also NMDA receptor gene expression in an other types of brain and spinal cord injury. If an individual individual. is heterozygous, then his or her risk of developing neuro degenerative disease is at an intermediate level. On the other 0578 Thus, in one aspect, the present invention encom hand, if the individual is homozygous with the genotype passes a method for predicting in an individual NARG2 EX 10(a)-23C/C, EX 12(a)48T/T, EX14(a)+15G/G, gene expression (mRNA and/or protein) level or NMDA EX16(a) 1757w/w, EX16(a)2306G/G, EX16(a)2547G/G and receptor (NMDAR1) expression level, and the biological, EX16(a)4025m/m, then it can be reasonably predicted that pharmacological or pharmacokinetic consequences thereof. the individual has a reduced Susceptibility to neurodegen 0579. In one embodiment, the present invention encom erative disease, particularly ALS, Parkinson's disease, passes a method for predicting the pharmacokinetic conse Alzheimer's disease and other types of brain and spinal cord quences of NMDA receptor expression, i.e., the responsive injury. ness of an individual to an NMDA receptor antagonist, or the dose of an NMDA receptor antagonist to be used in an 0581. In another aspect, the present invention provides a individual, or potential toxicity of an NMDA receptor method for identifying high-risk patients who have a poor antagonist on an individual, which can all correlate with the prognosis of neurodegenerative disease, or for the prognosis NMDA receptor expression level. In specific embodiments, of a neurodegenerative disease, or predicting/determining the individual is diagnosed of a disease, e.g., neurodegen the potential progression of a neurodegenerative disease. erative disease (particularly ALS, Parkinson's disease, The individual to be tested can be a healthy person or an Alzheimer's disease), epilepsy, stroke, and other types of individual diagnosed with a neurodegenerative disease. The brain and spinal cord injury. Specifically, if one or more the method comprises the step of genotyping the individual to SNPs EX10(a)-23A, EX12(a)48C, EX14(a)+15C, determine the individual’s genotype at one or more of the EX16(a) 1757m, EX16(a)2306C, EX16(a)2547T and loci identified in the present invention, namely EX10(a)-23, EX16(a)4025w are detected, or a SNP that is in linkage EX 12(a)48, EX14(a)+15, EX16(a) 1757, EX16(a)2306, disequilibrium with any one of such SNPs is detected in the EX16(a)2547 and EX16(a)4025, or another locus at which individual, then low expression of NARG2 and high expres the genotype is in linkage disequilibrium with one of the sion of NMDAR1 are predicted, and the pharmacokinetic SNPs of the present invention. Thus, if one or more the consequences are then predicted. More specifically, the SNPs EX10(a)-23A, EX12(a)48C, EX14(a)+15C, individual’s responsiveness to NMDA receptor antagonists EX16(a) 1757m, EX16(a)2306C, EX16(a)2547T and is predicted. Selection of patients for inclusion in clinical EX16(a)4025w are detected, or a SNP that is in linkage trials involving an NMDA receptor antagonist can be made disequilibrium with any one of such SNPs is detected in the based on the predicted NMDA receptor expression. In individual, then it can be reasonably predicted that the addition, whether or not to treat the individual with an individual has poor prognosis. In other words the individual NMDA receptor antagonist and the dosage or other treat has a high potential of neurodegenerative disease progres ment regimen to be used can also be decided based on the sion. Particularly, if an individual is homozygous with the SNP profile in NARG2 gene and the predicted NARG2 and genotype EX10(a)-23A/A, EX12(a)48C/C, EX14(a)+15C/C, NMDA receptor expression. For example, if a SNP associ EX16(a) 1757m/m, EX16(a)2306C/C, EX16(a)2547T/T and ated with low NARG2 expression and thus high NMDAR1 EX16(a)4025w/w, then the individual has particularly poor expression is detected in an individual, then a higher dosage prognosis. However, if an individual is heterozygous with or more frequent treatment may be administered to the the genotype EX10(a)-23A/C, EX12(a)48C/T, EX14(a)+ individual. 15C/G, EX16(a)1757m/w, EX16(a)2306C/G, EX16(a)2547T/G and EX16(a)4025w/m, then the individual 0580. In another aspect, the present invention encom has an intermediate level of risk of neurodegenerative dis passes a method for predicting or detecting Susceptibility to ease progression, especially associated with ALS, Parkin neurodegenerative disease in an individual, which comprises son's disease, Alzheimer's disease and other types of brain the step of genotyping the individual to determine the and spinal cord injury. That is, the risk is greater than a US 2007/0O82347 A1 Apr. 12, 2007 person having a homozygous genotype of EX10(a)-23C/C, 0585 Thus, in one aspect, the present invention encom EX 12(a)48T/T, EX14(a)+15G/G, EX16(a)1757w/w, passes a method for predicting in an individual DDX58 EX16(a)2306G/G, EX16(a)2547G/G and EX16(a)4025m/m, (RIG-1) gene expression (mRNA and/or protein) level, and but is lower than a person having a homozygous genotype of the biological, pharmacological or pharmacokinetic conse EX10(a)-23A/A, EX 12(a)48C/C, EX14(a)+15C/C, quences thereof. EX16(a) 1757m/m, EX16(a)2306C/C, EX16(a)2547T/T and 0586 Thus, in one aspect, the present invention encom EX16(a)4025w/w. passes a method for predicting or detecting cancer Suscep 0582 Thus, if the individual is homozygous with the tibility in an individual, which comprises the step of geno genotype EX10(a)-23C/C, EX12(a)48T/T, EX14(a)+15G/G, typing the individual to determine the individual’s genotype EX16(a) 1757w/w, EX16(a)2306G/G, EX16(a)2547G/G and at one or more of the loci identified in the present invention, EX16(a)4025m/m, then it can be reasonably predicted that namely EX14(a)+78 and EX17(a)63, or another locus at the neurodegenerative disease in the individual will progress which the genotype is in linkage disequilibrium with one of and that the individual has a good prognosis. That is, the the SNPs of the present invention. Thus, if one or more the individual does not have an increased risk or likelihood of SNPs EX14(a)+78T, EX17(a)63C are detected, or a SNP that neurodegenerative disease progression. is in linkage disequilibrium with any one of such SNPs is detected in the individual, then it can be reasonably pre 0583. In yet another aspect, the present invention pro dicted that the individual is at an increased risk of develop vides a method for predicting or detecting the ability to ing cancer, particularly skin cancer, lung cancer, ovarian recover from brain and spinal cord injury in an individual, cancer or thyoma. In particularly, if an individual is homozy which comprises the step of genotyping the individual to gous with the genotype EX14(a)+78T/T, EX17(a)63C/C, determine the individual’s genotype at one or more of the then it can be reasonably predicted that the individual has an loci identified in the present invention, namely EX10(a)-23, elevated susceptibility to cancer. If an individual is heterozy EX 12(a)48, EX14(a)+15, EX16(a) 1757, EX16(a)2306, gous, then his or her risk of developing cancer is at an EX16(a)2547 and EX16(a)4025, or another locus at which intermediate level. One the other hand, if the individual is the genotype is in linkage disequilibrium with one of the homozygous with the genotype EX14(a)+78C, EX17(a)63-A, SNPs or haplotypes of the present invention. Thus, if one or then it can be reasonably predicted that the individual has a more the SNPs EX10(a)-23C, EX12(a)48T, EX14(a)+15G, reduced Susceptibility to cancer. EX16(a) 1757w, EX16(a)2306G, EX16(a)2547G and 0587. In another aspect, the present invention provides a EX16(a)4025m are detected, or a SNP that is in linkage method for identifying high-risk patients who have a poor disequilibrium with any one of such SNPs is detected in the prognosis of cancer, or for the prognosis of cancer, or individual, then it can be reasonably predicted that the predicting/determining the invasiveness and metastatic individual has a higher expression of NARG2 and is less potential of tumor in a patient, particularly cancer patient, prone to neuronal differentiation, and has worse prognosis of e.g., with cancer Such as melanoma, colon cancer, lung recovering from brain and spinal cord injury. In particular, if cancer, ovarian cancer, non-Small cell lung cancers an individual is homozygous with the genotype EX10(a)- (NSCLCs), and thyoma. The individual to be tested can be 23C/C, EX12(a)48T/T, EX14(a)+15G/G, EX16(a)1757w/w, a healthy person or an individual diagnosed of cancer. In this EX16(a)2306G/G, EX16(a)2547G/G and EX16(a)4025m/m, aspect, in patients diagnosed with cancer, either normal then it can be reasonably predicted that the individual has a tissue or cells, or tumor tissue or cells can be used in high probability or likelihood of slow recovering from brain genotyping for germline genotype or Somatic genotype in and spinal cord injury. If an individual is heterozygous, then tumor samples. The method comprises the step of genotyp his or her likelihood of recovery is at an intermediate level. ing the individual to determine the individual’s genotype in On the other hand, if the individual is homozygous with the the sample at one or more of the loci identified in the present genotype EX10(a)-23A/A, EX12(a)48C/C, EX14(a)+15C/C, invention, namely EX14(a)+78 and EX17(a)63, or another EX16(a) 1757m/m, EX16(a)2306C/C, EX16(a)2547T/T and locus at which the genotype is in linkage disequilibrium with EX16(a)4025w/w, then it can be reasonably predicted that one of the SNPs of the present invention. Thus, if one or the NARG2 expression in the individual is lower and the more the SNPs EX14(a)+78T or EX17(a)63C are detected, or individual has high probability of recovering from brain and a SNP that is in linkage disequilibrium with any one of such spinal cord injury. SNPs is detected in the individual, then it can be reasonably DDX58 predicted that the individual has high metastasis potential, that the cancer has poor prognosis and that the tumor cells 0584) As indicated in Tables 27 and 73 below, the expres are invasive. In other words, the individual has an increased sion level of the DDX58 gene in human cells is an inherit likelihood or at an increased risk of cancer metastasis. able "quantitative trait” with genetic determinants. Further Particularly, if an individual is homozygous with the geno more, the SNPs and/or haplotypes in accordance with the type EX14(a)+78T/T or EX17(a)63C/C, then the individual present invention are associated with the "quantitative trait”. has particular poor prognosis and that the tumor cells are i.e., mRNA level of the DDX58 gene in human cells. highly invasive. In other words, the individual has a sub Specifically, the SNPs EX14(a)+78C and EX17(a)63A are stantially increased likelihood or at a Substantially increased associated with the “low expression phenotype' while the risk of cancer metastasis. However, if an individual is SNPs EX14(a)+78T, EX17(a)63C are associated with “high heterozygous with the genotype EX14(a)+78T/C or expression phenotype.” Thus, the SNPs are particularly EX17(a)63C/A, then the individual has poor prognosis and useful in predicting the DDX58 gene expression in an that the tumor cells are invasive. Specifically, the individual individual. Furthermore, other SNPs that are in linkage has an intermediate level of risk of cancer metastasis. That disequilibrium with the SNPs can also have similar predic is, the risk is greater than a person having a homozygous tive value. genotype of EX14(a)+78C/C or EX17(a)863A/A, but is US 2007/0O82347 A1 Apr. 12, 2007 72 lower than a person having a homozygous genotype of the dose of an anticancer agent or an antiviral agent to be EX 14(a)+78T/T or EX17(a)63C/C. used in an individual, or potential toxicity of an anticancer agent or an antiviral agent on an individual, which can all 0588 Thus, if the individual is homozygous with the correlate with the DDX58 or COX-2 expression level. In genotype EX14(a)+78C/C or EX17(a)63A/A, then it can be specific embodiments, the individual is diagnosed of a reasonably predicted that the tumor in the individual has low disease, e.g., cancer or viral infection (particularly infection metastasis potential, that the cancer has good prognosis and of a RNA virus, especially double-stranded RNA virus). that the tumor cells are not invasive. That is, the individual Specifically, if one or more of the SNPs EX14(a)+78C and does not have an increased likelihood or increased risk of EX17(a)63A are detected, or an LDSNP that is in linkage cancer metastasis. disequilibrium with any one of such SNPs is detected in the 0589. In another aspect, the present invention provides a individual, then low expression of DDX58 is predicted, and method for predicting in an individual immune response to the pharmacokinetic consequences are then predicted. More viral infection, particularly infection of RNA viruses, and specifically, the individual’s responsiveness to an anticancer more particularly double-stranded RNA viruses. The method or antiviral agent is predicted. Selection of patients for comprises the step of genotyping the individual to determine inclusion in clinical trials involving an anticancer (particu the individuals genotype at one or more of the loci identi larly COX-2 inhibitor or anti-DDX58) or antiviral agent fied in the present invention, namely EX14(a)+78 and (particularly RNA virus-specific antiviral agent) can be EX17(a)63, or another locus at which the genotype is in made based on the predicted DDX58 expression. In addi linkage disequilibrium with one of the SNPs or haplotypes tion, the dosage or other treatment regimen to be used can of the present invention. Thus, if one or more of the SNPs also be decided based on the SNP profile in DDX58 gene associated with high expression of DDX58 (EX14(a)+78T or and the predicted DDX58 expression. For example, if a SNP EX17(a)63C, or a SNP that is in linkage disequilibrium with associated with low DDX58 expression is detected in a any one of such SNPs) is present in the individual, then it cancer patient, then a lower dosage of, or less frequent will be reasonable to predict that the individual has an treatment with, a COX-2 inhibitor may be administered to increased likelihood of having a stronger immune response the individual in the cancer patient, but the cancer patient to viral infection, i.e., strong host antiviral response, par may be less responsive to a COX-2 or DDX58 inhibitor. If ticularly to double-stranded RNA viruses, e.g., paramyxovii a SNP associated with high DDX58 expression is detected, ruses, influenza virus and Japanese encephalitis virus. Such especially a homozygosity thereof, then a higher dosage of individuals will also have an increased resistance to viral or more frequent administration may be required, but the infection, particularly RNA viruses, e.g., paramyxoviruses, patient may be more responsive to a COX-2 or DDX58 HIV. HCV, influenza virus and Japanese encephalitis virus. inhibitor. In addition, individuals with Such genotypes will also have 0592. In another example, if a SNP associated with low an increased inflammatory response to viral infection, par DDX58 expression is detected in a patient, especially a ticularly double-stranded RNA viruses, e.g., paramyxovii homozygosity thereof, then a higher dosage of or more ruses, influenza virus and Japanese encephalitis virus. frequent treatment with, an antiviral agent may be required 0590 Thus, if one or more the SNPs EX14(a)+78C or for treating infection of a RNA virus. Particularly, a higher EX17(a)63A are detected, or a SNP that is in linkage dosage of interferon may be required. If a SNP associated disequilibrium with any one of such SNPs is detected in the with high DDX58 expression is detected, especially a individual, then it can be reasonably predicted that the homozygosity thereof, then the patient may require a lower individual will have a decreased resistance to viral infection, dosage of an antiviral agent, or less frequent administration more attenuated host antiviral response, decreased immune thereof. response to viral infection, and relatively lower inflamma CD39 tory response to viral infection, particularly double-stranded RNA viruses, e.g., paramyxoviruses, influenza virus and 0593. As indicated in Table 28 and 74, the expression Japanese encephalitis virus. In other words, the individual level of the CD39 gene in human cells is an inheritable has an increased likelihood of developing viral infection. “quantitative trait” with genetic determinants. Furthermore, Particularly, if an individual is homozygous with the geno the SNPs in accordance with the present invention are type EX14(a)+78C/C or EX17(a)63A/A, then the individual associated with the "quantitative trait”, i.e., expression level has particularly poor immune response and low inflamma of the CD39 gene in human cells. Specifically, the SNPs tory response to viral infection. However, if an individual is EX4(a)-10T and EX10(a)3061A are associated with the “low heterozygous with the genotype EX14(a)+78T/C or expression phenotype' while the SNPs EX4(a)-10C and EX17(a)63C/A, then the individual has intermediate resis EX10(a)3061G are associated with “high expression pheno tance to viral infection and inflammatory response. Alterna type.” Thus, the SNPs are particularly useful in predicting tively, if the individual is homozygous with the genotype the CD39 gene expression in an individual. Furthermore, EX14(a)+78T/T or EX17(a)63C/C, then it can be reasonably other SNPs that are in linkage disequilibrium with the SNPs predicted that the individual will have an increased resis can also have similar predictive value. tance to viral infection. In other word, the individual will have a reduced susceptibility viral infection, especially 0594 Thus, in one aspect of the invention a method is infection of double-stranded RNA viruses. provided for predicting or detecting Susceptibility to vascu lar injury in an individual, which comprises the steps of 0591. In yet another aspect, the present invention encom genotyping the individual to determine the individuals passes a method for predicting the pharmacokinetic conse genotype at one or more loci identified in the present quences of DDX58 expression, e.g., the responsiveness of invention wherein one or more of the SNPs associated with an individual to an anticancer agent or an antiviral agent, or low expression phenotype of CD39 are detected in the US 2007/0O82347 A1 Apr. 12, 2007

individual, then it can be predicted that the individual has an particular, if an individual is homozygous with the genotype increased risk of developing a metabolic or vascular disease. EX4(a)-10C/C or EX10(a)3061G/G, or a SNP that is in Thus, if one or more the SNPs EX4(a)-10T and linkage disequilibrium with any one or more of such SNPs, EX10(a)3061A in CD39 are detected, or an LDSNP that is then it can be reasonably predicted that the individual has a in linkage disequilibrium with any one of such SNPs is diminished risk of coronary disease. In other words, such an detected in the individual, then it can be reasonably pre individual has an decreased likelihood or is at an decreased dicted that the individual is at an increased risk of vascular risk of developing coronary disease. If an individual is injury. In particular, if an individual is homozygous with the heterozygous, then his or her risk of developing the disease genotype EX4(a)-10T/T or EX10(a)3061A/A, or homozy is at an intermediate level. On the other hand, if the gous with an LDSNP that is in linkage disequilibrium with individual is homozygous with the genotype EX4(a)-10T/T any one or more of such SNPs, then it can be reasonably or EX10(a)3061A/A, or a SNP that is in linkage disequilib predicted that the individual has a increased susceptibility to rium with any one or more of such SNPs, then it can be vascular injury. In other words, Such an individual has an reasonably predicted that the individual has an elevated increased likelihood or is at an increased risk of developing Susceptibility to coronary disease. vascular disease or vascular injury. If an individual is 0597. In another aspect, the present invention provides a heterozygous, then his or her risk of developing the disease method for identifying patients with a high risk of transplant is at an intermediate level. On the other hand, if the rejection. The individual to be tested can be a healthy individual is homozygous with the genotype EX4(a)-10C/C individual or an individual in need of a transplant. The and EX10(a)3061G/G, or a SNP that is in linkage disequi method comprises the step of genotyping the individual to librium with any one or more of such SNPs, then it can be determine the individual’s genotype at one or more of the reasonably predicted that the individual has a reduced sus loci identified in the present invention, namely EX4(a)-10 ceptibility to vascular injury. and EX10(a)3061 in CD39, or another locus at which the 0595. In another aspect, the present invention provides a genotype is in linkage disequilibrium with one of the SNPs method for determining the prognosis of an individual with of the present invention. Thus, if one or more the SNPs vascular injury. The individual to be tested can be a healthy EX4(a)-10C and EX10(a)3061G are detected, or an LDSNP person or previously diagnosed individual. The method that is in linkage disequilibrium with any one of such SNPs comprises the step of genotyping the individual to determine is detected in the individual, then it can be reasonably the individuals genotype at one or more of the loci identi predicted that the individual has low transplant rejection fied in the present invention, or another locus at which the risk. Particularly, if an individual is homozygous with the genotype is in linkage disequilibrium with one of the SNPs genotype EX4(a)-10C/C or EX10(a)3061G/G, then the indi of the present invention. Thus, if one or more the SNPs vidual has particular low risk of transplant rejection. How EX4(a)-10T or EX10(a)3061A are detected, or an LDSNP ever, if an individual is heterozygous with the genotype that is in linkage disequilibrium with any one of such SNPs EX4(a)-10T/C or EX10(a)3061A/G, then the individual has is detected in the individual, then it can be reasonably an intermediate risk of transplant rejection. Thus, if the predicted that the individual has a high potential of disease individual is homozygous with the genotype EX4(a)-10T/T progression and that the prognosis for the individual is poor, or EX10(a)3061A/A, or a homozygous LDSNP thereof then or recovery is difficult or slow. In other words, the individual it can be reasonably predicted that the individual has a has an increased likelihood or an increased risk of disease particularly increased risk of transplant rejection. progression. Particularly, if an individual is homozygous with the genotype EX4(a)-10T/T or EX10(a)3061A/A, or a 0598. For example, in one embodiment, selection of a SNP that is in linkage disequilibrium with any one or more donor of transplant organ or tissue is aided by genotyping a of such SNPs, then the individual has particular poor prog donor candidate and determining the determine the individu nosis and that the disease will progress at an increased rate. als genotype at one or more of the loci identified in the In other words, the individual has a substantially increased present invention, namely EX4(a)-10 and EX10(a)3061 in likelihood or at a substantially increased risk of disease CD39, or another locus at which the genotype is in linkage progression. However, if an individual is heterozygous with disequilibrium with one of the SNPs of the present inven the genotype EX4(a)-10T/C or EX10(a)3061A/G, or is het tion. Specifically preferred donors should have a homozy erozygous with a SNP that is in linkage disequilibrium with gous EX4169 -10C/C or EX10(a)3061G/G, or a homozy any one or more of such SNPs, then the individual has a poor gous LD SNP thereof. Individuals with a homozygous prognosis. Specifically, the individual has an intermediate EX4(a)-10T/T or EX10(a)3061A/A, or a homozygous LD level of disease progression. SNP thereof are preferably excluded as organ or tissue 0596) In another aspect of the invention a method is transplant donors. provided for predicting or detecting Susceptibility coronary 0599. In another aspect, the present invention provides a disease in an individual, which comprises the steps of method for predicting and/or determining inflammatory genotyping the individual to determine the individuals response, particularly to irritants and immunogens. The genotype at one or more loci identified in the present method comprises the step of genotyping the individual to invention wherein one or more of the SNPs are detected in determine the individual’s genotype at one or more of the the individual, then it can be predicted that the individual has loci identified in the present invention, namely EX4(a)-10 an increased risk of developing a metabolic or vascular and EX10(a)3061 in CD39, or another locus at which the disease. Thus, if one or more the SNPs EX4(a)-10C and genotype is in linkage disequilibrium with one of the SNPs EX10(a)3061G are detected, or a SNP that is in linkage of the present invention. Thus, if the SNP EX4(a)-10T or disequilibrium with any one of such SNPs is detected in the EX10(a)3061A is detected, or an LDSNP that is in linkage individual, then it can be reasonably predicted that the disequilibrium with either of the SNPs is detected in the individual is at a decreased risk of coronary disease. In individual, then it can be reasonably predicted that the US 2007/0O82347 A1 Apr. 12, 2007 74 individual will have an increased inflammatory response, nerve damage, which comprises the steps of genotyping and particularly in response to irritants and immunogens. Par determining the FKBP1 a genotype of the individual at ticularly, if an individual is homozygous with the genotype EX5(a)8. The individual to be tested can be a healthy person EX4(a)-10T/T or EX10(a)3061A/A, then the individual has or previously diagnosed individual. Thus, if the FKBP1a particularly high inflammatory response. However, if an SNP EX5(a)8G is detected, or an LDSNP that is in linkage individual is heterozygous with the genotype EX4(a)-10T/C disequilibrium with such SNP is detected in the individual, or EX10(a)3061A/G, then the individual has intermediate then it can be reasonably predicted that the individual has level of inflammatory response. Alternatively, if the indi low potential of recovery from nerve damage and/or vidual is homozygous with the genotype EX4(a)-10C/C or decreased nerve regeneration and that the prognosis for the EX10(a)3061G/G, then it can be reasonably predicted that individual is poor. Particularly, if an individual is homozy the individual will have a decreased inflammatory response, gous with the FKBP1a genotype EX5(a)8G/G, or a SNP that especially in response to irritants and immunogens. Such is in linkage disequilibrium with such SNP, then the indi prediction can be used in, e.g., determining the degree of vidual has particularly poor prognosis and that the regen harm of irritants and immunogens to a particular individual, eration will progress at a decreased rate. If an individual is and deciding on whether to administer an immunogen or heterozygous with the FKBP1a genotype EX5(a)A/G, or is vaccine to an individual and whether to include an indi heterozygous with a SNP that is in linkage disequilibrium vidual to a clinical trial particularly a clinical trial involving with SNP then the individual has a moderately poor prog an immunogen or Vaccine. nosis. Specifically, the individual has an intermediate rate of nerve regeneration. However, an individual homozygous 0600. In yet another aspect, the present invention encom with the FKBP1 a genotype EX5(a)A/A will have improved passes a method for predicting the pharmacokinetic conse recovery from nerve damage and increased rate of nerve quences of CD39 expression, e.g., the responsiveness of an regeneration following damage, and thus a better prognosis. individual to a drug, or the dose of a drug to be used in an individual, or potential toxicity of a drug on an individual, 0605. In another aspect of the invention, a method is which can all correlate with the CD39 expression level. provided for predicting or detecting response to treatment with macrollide immunosuppressant drugs such as rapamy 0601. In another aspect, the present invention relates a cin and FK506, which comprises the steps of genotyping the method of selecting individuals for inclusion in clinical individual to determine the individuals FKBP1a genotype trials. Such clinical trials can be on any drugs or medical or at the SNP identified in the present invention, wherein Surgical procedures in which platelet aggregation, vascular detection of the SNP in the individual is useful in predicting injury, organ or tissue transplantation, or inflammatory that the individual has an increased or decreased response to response is a relevant factor for safety or efficacy concerns. macrollide immunosuppressant drugs such as rapamycin and Thus, the method generally comprises genotyping an indi FK506 treatment, particularly in an individual diagnosed vidual to determine the genotype at one or more of the loci with cancer. Thus, if the FKBP1a SNPEX5(a)8A is detected, identified in the present invention, namely EX4(a)-10 and or a SNP that is in linkage disequilibrium with such SNP is EX10(a)3061 in CD39, or another locus at which the geno detected in the individual, then it can be reasonably pre type is in linkage disequilibrium with one of the CD39 SNPs dicted that the individual will have an increased response to of the present invention, and considering the genotype in macrollide immunosuppressant drugs such as rapamycin and making a decision as to whether or not to include the FK506 treatment. In particular, if an individual is homozy individual in a clinical trial. gous with the FKBP1a genotype EX5(a)8A/A, oran LDSNP that is in linkage disequilibrium with this SNP, then it can be 0602) The SNPs on Chromosome X at position 97.374, reasonably predicted that the macrollide immunosuppressant 982 and position 97.536,166 have also been shown to be drug treatment will have an increased effectiveness in the associated with CD39 mRNA levels. The Chromosome X individual. In other words. Such an individual has an SNPs associated with lower CD39 mRNA expression levels increased likelihood of successful treatment with macrollide are 97,374,982G and 97.536,166G, whereas that associated immunosuppressant drugs such as rapamycin and FK506 with higher mRNA expression levels are 97.374,982A and treatment. If an individual is heterozygous, then his or her 97.536,166C. In addition to those mentioned above, these response to macrollide immunosuppressant drug treatment is SNPs may be utilized in the applications described above. predicted to be intermediate. On the other hand, if the FKABP1a individual is homozygous with the FKBP1 a genotype EX5(a)8G/G, or a SNP that is in linkage disequilibrium with 0603 As indicated in Table 30 and 75, the expression such SNP, then it can be reasonably predicted that treatment level of the FKBP1 a gene in human cells is an inheritable with macrollide immunosuppressant drugs such as rapamy “quantitative trait” with genetic determinants. Furthermore, cin and FK506 will have decreased effectiveness and the the SNPs in accordance with the present invention are individual will have a diminished response to treatment. The associated with the “quantitative trait”, i.e., FKBP1 a mRNA predicted response can be used as a criterion in deciding levels in human cells. Specifically, the SNP EX5(a)8G is whether or how much to use a macrollide immunosuppres associated with a “low expression phenotype' while the SNP sant drug on a particular individual, and in deciding whether EX5(a)8A is associated with a “high expression phenotype.” to include an individual in a clinical trial in which FKBP1a Thus, the SNPs are particularly useful in predicting the level gene expression is a factor affecting safety or efficacy, or in of FKBP1 a gene expression in an individual. Furthermore, which a macrollide immunosuppressant drug is involved. other SNPs that are in linkage disequilibrium with these 0606. Thus, the present invention also provides a method SNPs can also have similar predictive value. of treating a patient with cancer comprising genotyping the 0604. In one aspect, the present invention provides a patient in the FKBP1 a gene to predict the patient’s response method for determining the prognosis of an individual with to treatment with macrollide immunosuppressant drugs such US 2007/0O82347 A1 Apr. 12, 2007 as rapamycin and FK506, and deciding on whether to their cancer cells, then it can be reasonably predicted that the administer a macrollide immunosuppressant drug to the individual has a low rate of remission. Particularly, if an patient. individual, or their cancer, is homozygous with the SRI genotype EX9(a)351T/T, then the individual has particularly SRI low rate of remission. However, if an individual, or their 0607 As indicated in Table 31 and 76, the expression cancer, is heterozygous with the genotype EX9(a)351T/C, level of the SRI gene in human cells is an inheritable then the individual has an intermediate cancer remission “quantitative trait” with genetic determinants. Furthermore, rate, especially that associated with AML. That is, cancer the SNP in accordance with the present invention is asso remission rate is increased in a individual having a homozy ciated with the "quantitative trait”, i.e., SRI mRNA levels in gous SRI genotype of EX9(a)351C/C in their somatic tissues human cells. Specifically, the SNPEX9(a)351C is associated or in their cancer, but is decreased in an individual having a with a “low expression phenotype' while the SNP homozygous SRI genotype of EX9(a)351T/T. EX9(a)351T is associated with a “high expression pheno 0610. In yet another aspect, the present invention pro type.” Thus, the SNPs are particularly useful in predicting vides a method of predicting patient response to cancer the level of SRI gene expression in an individual. Further treatment, especially to treatment with chemotherapeutics more, other SNPs that are in linkage disequilibrium with the that inhibit DNA synthesis (such as doxorubicin and etopo SNP can also have similar predictive value. side), inhibit protein synthesis (Such as homoharringtonine) and antimicrotubule agents (such as Vincristine). In accor 0608. In another aspect, the present invention provides a dance with the present invention, the SRI gene of a patient method for identifying high-risk patients who have a poor in need of chemotherapeutic treatment is genotyped in their prognosis of cancer, or for determining the prognosis of healthy tissues or in a biopsy sample of their cancer cells, to cancer, particularly in a cancer patient, e.g., with cancer Such determine the genotype at the EX9(a)351 locus of the present as acute myeloid leukemia (AML). The individual to be invention, specifically EX9(a)351, or another locus at which tested can be a healthy person or an individual diagnosed of the genotype is in linkage disequilibrium with EX9(a)351 of cancer. The genotyping can be performed on a healthy tissue the present invention. Expression levels of SRI can be sample or a tumor sample to determine germline or Somatic utilized to predict the effectiveness of treatment in a patient. genotype. For example, the method can comprise the steps Further, the amount of resistance will be indicative success of genotyping the Somatic tissues of an individual, and ful recovery of a patient undergoing radiation therapy. If the genotyping the cancer cells of that individual, to determine SNP EX9(a)351T are detected, or a SNP that is in linkage the genotype the SRI loci identified in the present invention, disequilibrium with any one of such SNP is detected in an namely EX9(a)351, or another locus at which the genotype individual or their cancer, then it can be reasonably predicted is in linkage disequilibrium with the SNP of the present that the cancer is more likely to be resistant cancer treatment invention. Thus, if the SRI SNP EX9(a)351T is detected, or using chemotherapeutics. In short, the individual will have a SNP that is in linkage disequilibrium with EX9(a)351T is a worse response, longer recovery time and poor prognosis. detected in the individual, particularly within the cancer In the event that the individual has the SRI genotype cells, then it can be reasonably predicted that the cancerous EX9(a)351T/T, it can be reasonably predicted that the indi growth or tumor has high metastatic potential, that the vidual will have a decreased response to cancer treatment patient has poor prognosis, and that the tumor cells of the using chemotherapeutics. If the individual is heterozygous, cancer are likely invasive. In other words, the individual has it can be predicted that the individual will have an interme an increased likelihood or is at an increased risk of cancer diate response to treatment. On the other hand, where an metastasis. Particularly, if an individual or their cancer is individual has the SRI genotype EX9(a)351C/C, then it can homozygous with the SRI genotype EX9(a)351T/T, then the be reasonably predicted that the individual will have individual has particularly poor prognosis and the cancer decreased resistance to cancer treatment involving chemo cells are likely highly invasive and give to rapid growth. therapeutics. However, if an individual, or their cancer, is heterozygous with the SRI genotype EX9(a)351T/C, then the individual 0611. In yet another aspect, the present invention encom has a moderately poor prognosis and the tumor cells are passes a method for predicting or detecting an individuals moderately invasive. Specifically, the individual has an ability to recover from heart disease, especially cardiomy intermediate level of risk of cancer metastasis, especially opathy, which comprises the step of genotyping the indi that associated with AML. That is, the clinical outcome is vidual to determine the individual’s genotype the SRI loci worse than a person having a homozygous SRI genotype of identified in the present invention, namely EX9(a)351, or EX9(a)351C/C, but is better than a person having a homozy another locus at which the genotype is in linkage disequi gous SRI genotype of EX9(a)351T/T. librium with the SNP of the present invention. Thus, if the SRISNPEX9(a)351C is detected, or a SNP that is in linkage 0609. In another aspect, the present invention provides a disequilibrium with the SNP is detected in the individual, method for predicting cancer remission rates in an individual then it can be reasonably predicted that the individual will diagnosed with cancer, especially acute myeloid leukemia have a decreased recovery rate for cardiovascular disease, (AML). The method comprises the steps of genotyping the especially for cardiomyopathy. In particular, if an individual healthy tissues of an individual, or the cancer cells of that is homozygous with the SRI genotype EX9(a)351C/C, then individual, to determine the genotype the SRI loci identified it can be reasonably predicted that the individual has a low in the present invention, namely EX9(a)351, or another locus ability to recover from cardiovascular disease. On the other at which the genotype is in linkage disequilibrium with the hand, if the individual is homozygous with the SRI genotype SNP of the present invention. Thus, if the SRI SNP EX9(a)351T/T, then it can be reasonably predicted that the EX9(a)351T is detected, or a SNP that is in linkage disequi individual has an increased ability to recover from cardio librium with EX9(a)351T is detected in the individual or vascular disease. US 2007/0O82347 A1 Apr. 12, 2007 76

0612 The predicted response can be used as a criterion in IRF5 deciding whether or how much to use a drug on a particular individual, and in deciding whether to include an individual 0617. As indicated in Tables 33, 78 and 79, the expres in a clinical trial in which SRI gene expression is a factor sion level of the IRF5 gene in human cells is an inheritable affecting safety or efficacy. “quantitative trait” with genetic determinants. Furthermore, the SNPs in accordance with the present invention are XRRA1 associated with the “quantitative trait”, i.e., IRF5 mRNA 0613. As indicated in Table 32 and 77, the expression levels in human cells. Specifically, the SNPs EX1(a)-709G, level of the XRRA1 gene in human cells is an inheritable EX1(a)-396C, EX1(a)-82m, EX6(a)91m, EX9(a)801A and “quantitative trait” with genetic determinants. Furthermore, EX9(a)862A are associated with a “low expression pheno the SNPs and/or haplotypes in accordance with the present type' while the EX1(a)-709T EX1(a)-396T, EX1(a)-82w, invention are associated with the "quantitative trait”, i.e., EX6(a)91w, EX9(a)801G and EX9(a)862G are associated XRRA1 mRNA level in human cells. Specifically, the SNPs with a “high expression phenotype.” Thus, the SNPs are EX2(a)26C, EX2(a)+40C, EX11(a)51C, EX13(a)62C and particularly useful in predicting the level of IRF5 gene EX17(a)665G are associated with a “low expression pheno expression in an individual. type' while the SNPs EX2(a)26G, EX2(a)+40T, EX11(a)51T, 0618. Thus, in one aspect, the present invention provides EX13(a)62G and EX17(a)665A are associated with a “high a method for predicting or determining immune response to expression phenotype.” Thus, the SNPs are particularly viral infection in an individual. The method comprises the useful in predicting the level of XRRA1 gene expression in step of genotyping the individual to determine the individu an individual. Furthermore, other SNPs that are in linkage als genotype at one or more of the IRF5 loci identified in the disequilibrium with the SNPs can also have similar predic present invention, namely EX1(a)-709, EX1(a)-39C, tive value. EX1(a)-82, EX6(a)91, EX9(a801 or EX9(a862, or another 0.614. In one aspect, the present invention encompasses a locus at which the genotype is in linkage disequilibrium with method for predicting or detecting sensitivity to ionizing one of the SNPs or haplotypes of the present invention. radiation in an individual, which comprises the step of Thus, if one or more the SNPs EX1(a)-709G, EX1-396C, genotyping the individual to determine the individuals EX1(a)-82m, EX6(a)91 m, EX9(a)801A or EX9(a)862A are genotype at one or more of the XRRA1 loci identified in the detected, or a SNP that is in linkage disequilibrium with any present invention, namely EX2(a)26, EX2(a)+40, EX15(a).51, one of such SNPs is detected in the individual, then it can be EX13(a)62 and EX17(a)665, or another locus at which the reasonably predicted that the individual will have a dimin genotype is in linkage disequilibrium with one of the SNPs ished immune response. In other words, the individual has of the present invention. The genotyping can be performed an increased likelihood of developing viral infection. Par on a healthy tissue sample or a disease tissue sample (e.g., ticularly, if an individual is homozygous with the IRF5 tumor sample) to determine germline or somatic genotype. genotype EX1(a)-709G/G, EX1(a)-396C/C, EX1(a)-82m/ Thus, if one or more the XRRA1 SNPs EX2(a)26G, EX2(a)+ m, EX6(a)91m/m, EX9(a801A/A or EX9(a)862A/A, then the 40T, EX11(a)51T, EX13(a)62G and EX17(a)665A are individual has particularly poor immune response, espe detected, or a SNP that is in linkage disequilibrium with any cially to viral infection. However, if an individual is het one of such SNPs is detected in the individual, then it can be erozygous with the IRF5 genotype EX1(a)-709G/T, EX1(a)- reasonably predicted that the individual has increased sen 396C/T, EX1(a)-82m/w, EX6(a)91m/w, EX9(a)801A/G or sitivity to ionizing radiation. In particularly, if an individual EX9(a)862A/G, then the individual has intermediate is homozygous with the XRRA1 genotype EX2(a)26G/G, immune response. Specifically, the individual has an inter EX2(a)+40T/T, EX11(a)51T/T, EX13(a)62G/G and mediate level of risk of viral infection. Alternatively, if the EX17(a)665A/A, then it can be reasonably predicted that the individual is homozygous with the IRF5 genotype EX1(a)- individual has an increased sensitivity to ionizing radiation. 709T/T, EX1(a)-396T/T, EX1(a)-82w/w, EX6(a)91 w/w, If an individual is heterozygous with the XRRA1 genotype EX9(a)801G/G or EX9(a)862G/G, then it can be reasonably EX2(a)26G/C, EX2(a)+40T/C, EX11(a)51T/C, predicted that the individual will have a good immune EX13(a)62G/C and EX17(a)665A/G, then his or her sensi response. In other word, the individual will have a reduced tivity to radiation therapy is at an intermediate level. One the susceptibility to infection, especially viral infection. other hand, if the individual is homozygous with the XRRA1 genotype EX2(a)26C/C, EX2(a)+40C/C, EX11(a)51C/C, 0619. In another aspect, the present invention provides a EX13(a)62C/C and EX17(a)665G/G, then it can be reason method for identifying high-risk patients who have a poor ably predicted that the individual has a decreased sensitivity prognosis of viral infection, or predicting/determining the to ionizing radiation. invasiveness and viral progression in an individual. The individual to be tested can be a healthy person or an 0615. The predicted XRRA1 expression level and sensi individual diagnosed with viral infection. The method com tivity to ionizing radiation can be used as a criterion in prises the step of genotyping the individual to determine the deciding whether or how much to use ionizing radiation on individual’s genotype at one or more of the IRF5 loci a particular individual, and in deciding whether to include an identified in the present invention, namely EX1(a)-709, individual in a clinical trial in which XRRA1 gene expres EX1(a)-39C, EX1(a)-82, EX6(a)91, EX9(a)801 or sion is a factor affecting safety or efficacy, or involving EX9(a)862, or another locus at which the genotype is in ionizing radiation. linkage disequilibrium with one of the SNPs of the present 0616) Thus, a treatment method is provided comprising invention. Thus, if one or more the IRF5 SNPs EX1(a)- genotyping the patient in the XRRA1 gene to predict the 709G, EX1(a)-396C, EX1(a)-82m, EX6(a).91m. patient’s sensitivity to treatment with ionizing radiation, and EX9(a)801A or EX9(a)862A are detected, or a SNP that is in deciding on whether to treat the patient with ionizing linkage disequilibrium with any one of such SNPs is radiation or the dose thereof. detected in the individual, then it can be reasonably pre US 2007/0O82347 A1 Apr. 12, 2007 77 dicted that the individual has a poor prognosis for viral ease, particularly Wegener's granulomatosis, multiple scle infection, or a poor prognosis for viral invasiveness and rosis, type 1 diabetes mellitus, lupus, and rheumatoid arthri progression. In other words, the individual has an increased tis. Similarly, if the individual is homozygous with a likelihood or at an increased risk of viral infection. Particu genotype at a locus that is in the same haplotype with the larly, if an individual is homozygous with the IRF5 genotype IRF5 SNPs EX1(a)-709G, EX1(a)-396C, EX1(a)-82m, EX1(a)-709G/G, EX 1-396C/C, EX1(a)-82m/m, EX6(a)91m, EX9(a)801A or EX9(a)862A(in linkage disequi EX6(a)91m/m, EX9(a)801A/A or EX9(a)862A/A, then the librium), then it can reasonably be predicted that the indi individual has particular poor prognosis. In other words, the vidual has a reduced Susceptibility to autoimmune disease, individual has a substantially increased likelihood or at a particularly Wegener's granulomatosis, multiple Sclerosis, Substantially increased risk of viral progression after infec type 1 diabetes mellitus, lupus, and rheumatoid arthritis. tion. However, if an individual is heterozygous with the IRF5 genotype EX1(a)-709G/T, EX1(a)-396C/T, EX1(a)- 0621. The SNP at position 128,208,314 of chromosome 82m/w, EX6(a)91m/w, EX9(a)801A/G or EX9(a)862A/G, 7, has also shows association with IRF5 mRNA expression then the individual has an intermediate risk of viral progres levels. In addition to those mentioned above, these SNPs sion. Thus, if the individual is homozygous with the IRF5 may be utilized in the applications described above. genotype EX1(a)-709T/T, EX1(a)-396T/T, EX1(a)-82w/w, AMFR EX6(a)91 w/w, EX9(a)801 G/G or EX9(a862G/G, then it can be reasonably predicted that individual will have a good 0622. As indicated in Table 34, 35 and 80, the expression prognosis. That is, the individual does not have an increased level of the AMFR gene in human cells is an inheritable likelihood or increased risk of viral progression after infec “quantitative trait” with genetic determinants. Furthermore, tion. the SNPs and/or haplotypes in accordance with the present invention are associated with the "quantitative trait”, i.e., 0620. In another aspect, the present invention encom AMFR mRNA levels in human cells. Specifically, the SNPs passes a method for predicting or detecting Susceptibility to in Haplotype I (e.g., EX4(a)+14T, EX12(a)+62A, autoimmune disease in an individual, which comprises the EX14(a) 1359C) and the SNP EX14(a)483G are associated step of genotyping the individual to determine the individu with a “low expression phenotype' while the SNPs in als genotype at one or more of the IRF5 loci identified in the Haplotypes II (e.g., EX4(a)+14C, EX12(a)+62G, present invention, namely EX1(a)-709, EX1(a)-39C, EX14(a) 1359T) and the SNP EX14(a)483A are associated EX1(a)-82, EX6(a)91, EX9(a)801 or EX9(a862, or another with a “high expression phenotype.” Thus, the SNPs and/or locus at which the genotype is in linkage disequilibrium with haplotypes are particularly useful in predicting the level of one of the SNPs or haplotypes of the present invention. AMFR gene expression in an individual. Furthermore, other Thus, if one or more the IRF5 SNPs EX1(a)-709T EX1(a)- SNPs that are in linkage disequilibrium with the SNPs 396T, EX1(a)-82w, EX6(a)91w, EX9(a)801G and and/or haploytes can also have similar predictive value. EX9(a)862G are detected, or a SNP that is in linkage disequilibrium with any one of such SNPs is detected in the 0623 Thus, in one aspect, the present invention encom individual, then it can be reasonably predicted that the passes a method for predicting or detecting cancer Suscep individual is at an increased risk of developing an autoim tibility in an individual, which comprises the step of geno mune disease, particularly Wegener's granulomatosis, mul typing the individual to determine the individual’s genotype tiple Sclerosis, type 1 diabetes mellitus, lupus, and rheuma at one or more of the AMFR loci identified in the present toid arthritis. In particularly, if an individual is homozygous invention, namely EX4(a)+14, EX12(a)+62, EX14(a) 1359 with the IRF5 genotype EX1(a)-709T/T, EX1(a)-396T/T, and EX14(a)483, or another locus at which the genotype is EX1(a)-82w/w, EX6(a)91 w/w, EX9(a)801G/G or in linkage disequilibrium with one of the SNPs or haplo EX9(a)862G/G, then it can be reasonably predicted that the types of the present invention. Thus, if one or more the individual has an elevated Susceptibility to autoimmune AMFR SNPs EX4Q)+14C, EX12(a)+62G, EX14(a) 1359T disease, particularly Wegener's granulomatosis, multiple and SNP EX14(a)483A are detected, or a SNP that is in Sclerosis, type 1 diabetes mellitus, lupus, and rheumatoid linkage disequilibrium with any one of such SNPs is arthritis. Likewise, if the individual is homozygous with a detected in the individual, then it can be reasonably pre IRF5 genotype at a locus that is in the same haplotype with dicted that the individual is at an increased risk of develop the SNPs EX1(a)-709T/T, EX1(a)-396T/T, EX1(a)-82w/w, ing cancer, particularly skin cancer, lung cancer, ovarian EX6(a)91 w/w, EX9(a)801G/G or EX9(a)862G/G (in linkage cancer or thyoma. In particularly, if an individual is homozy disequilibrium), then it can reasonably be predicted that the gous with the AMFR genotype EX4(a)+14C/C, EX12(a)+ individual has an elevated Susceptibility to autoimmune 62G/G, EX14(a) 1359T/T or EX14(a)483A/A, then it can be disease, particularly Wegener's granulomatosis, multiple reasonably predicted that the individual has an elevated Sclerosis, type 1 diabetes mellitus, lupus, and rheumatoid Susceptibility to cancer, particularly skin cancer (e.g., mela arthritis. In other words. Such an individual has an increased noma), lung cancer (e.g., NSCLCs), ovarian cancer or likelihood or is at an increased risk of developing autoim thyoma. Likewise, if the individual is homozygous with an mune disease, particularly Wegener's granulomatosis, mul AMFR genotype at a locus that is in the same haplotype with tiple Sclerosis, type 1 diabetes mellitus, lupus, and rheuma the SNPs EX4(a)+14C, EX12(a)+62G and EX14(a) 1359T (in toid arthritis. If an individual is heterozygous, then his or her linkage disequilibrium), or in linkage disequilibrium with risk of developing autoimmune disease is at an intermediate the SNP EX14(a)483A, then it can reasonably be predicted level. One the other hand, if the individual is homozygous that the individual has an elevated susceptibility to cancer, with the IRF5 genotype EX1(a)-709G/G, EX1(a)-396C/C, particularly skin cancer (e.g., melanoma), lung cancer (e.g., EX1(a)-82m/m, EX6(a)91m/m, EX9(a)801A/A or NSCLCs) or thyoma. In other words, such an individual has EX9(a)862A/A, then it can be reasonably predicted that the an increased likelihood or is at an increased risk of devel individual has a reduced susceptibility to autoimmune dis oping cancer, particularly skin cancer (e.g., melanoma), lung US 2007/0O82347 A1 Apr. 12, 2007

cancer (e.g., NSCLCs) or thyoma. If an individual is het the SNPs EX4(a)+14T, EX12(a)+62A and EX14(a) 1359C (in erozygous, then his or her risk of developing cancer is at an linkage disequilibrium), or in the same haplotype (linkage intermediate level. One the other hand, if the individual is disequilibrium) with the SNP EX14(a)483G, then it can homozygous with the AMFR genotype EX4(a)+14T/T or reasonably be predicted that the individual has a low EX 12(a)+62A/A or EX14(a) 1359C/C or EX14(a)483G/G, metastasis potential, that the cancer has good prognosis and then it can be reasonably predicted that the individual has a that the tumor cells are not invasive. In other words, the reduced Susceptibility to cancer, particularly skin cancer, individual does not have an increased likelihood or lung cancer, ovarian cancer or thyoma. Similarly, if the increased risk of cancer metastasis. individual is homozygous with a genotype at an AMFR locus that is in the same haplotype with the SNPs EX4(a)+ 0626. In another aspect, the present invention provides a 14T, EX12(a)+62A and EX14(a) 1359C (in linkage disequi method for identifying high-risk patients who have cancer librium), or in the same haplotype (linkage disequilibrium) ous growths or tumors, and who have a poor prognosis of with the SNP EX14(a)483G, then it can reasonably be recovery, or for predicting/determining the invasiveness and predicted that the individual has a reduced susceptibility to metastatic potential of the cancerous growth or tumor within cancer, particularly skin cancer, lung cancer or thyoma. a patient, particularly cancer patient, e.g., with melanoma, 0624. In another aspect, the present invention provides a lung cancer, ovarian cancer, non-Small cell lung cancers method for identifying high-risk patients who have a poor (NSCLCs), or thyoma. In this aspect of the invention, the prognosis of cancer, or for the prognosis of cancer, or methods comprise the step of genotyping the cancerous predicting/determining the invasiveness and metastatic growth or tumor within the individual to determine the potential of tumor in a patient, particularly cancer patient, cancerous growth or tumors genotype at one or more of the e.g., with cancer Such as melanoma, lung cancer, ovarian AMFR loci identified in the present invention, namely those cancer, non-Small cell lung cancers (NSCLCs), and thyoma. The individual to be tested can be a healthy person or an listed above, or another locus at which the genotype is in individual diagnosed of cancer. The method comprises the linkage disequilibrium with one of the SNPs of the present step of genotyping the individual to determine the individu invention. als genotype at one or more of the AMFR loci identified in 0627 Particularly, if the tumor or cancerous growth turns the present invention, namely EX4(a)+14, EX12(a)+62. out to be homozygous with the AMFR genotype EX4(a)+ EX14(a) 1359 and EX14(a)483, or another locus at which the 14C/C, EX12(a)+62G/G, EX14(a) 1359T/T or SNP genotype is in linkage disequilibrium with one of the SNPs EX14(a)483A/A, then the tumor or cancerous growth is or haplotypes of the present invention. Thus, if one or more likely highly invasive, and the patient has a particularly poor the AMFR SNPs EX4(a)+14C, EX12(a)+62G, EX14(a) 1359T and SNPEX14(a)483Aare detected, or a SNP prognosis. In other words, the patient has a Substantially that is in linkage disequilibrium with any one of such SNPs increased likelihood or at a substantially increased risk of is detected in the individual, then it can be reasonably cancer metastasis because the tumor has a genotype predicted that the individual has high metastasis potential, expected to overexpress AMFR. However, the tumor or that the cancer has poor prognosis and that the tumor cells cancerous growth turns out to be heterozygous with the are invasive. In other words, the individual has an increased AMFR genotype EX4(a)+14T/C, EX12(a)+62A/G, likelihood or at an increased risk of cancer metastasis. EX14(a) 1359C/T or SNP EX14(a)483G/A, then the tumor or Particularly, if an individual is homozygous with the AMFR cancerous growth is likely moderately invasive, and the genotype EX4(a)+14C/C, EX12(a)+62G/G, EX14(a) 1359T/T patient has an intermediate prognosis. Specifically, the or SNP EX14(a)483A/A, then the individual has particular patient has an intermediate level of risk of cancer metastasis. poor prognosis and that the tumor cells are highly invasive. That is, the risk is greater than a patient having a tumor or In other words, the individual has a substantially increased cancerous growth that has a homozygous AMFR genotype likelihood or at a substantially increased risk of cancer of EX4(a)+14T/T or EX12(a)+62A/A or EX14(a)1359C/C or metastasis. However, if an individual is heterozygous with EX14(a)483G/G, but is lower than a patient having a tumor the AMFR genotype EX4(a)+14T/C, EX12(a)+62A/G, or cancerous growth that homozygous genotype of EX4(a)+ EX 14(a) 1359C/T or SNP EX14(a)483G/A, then the indi 14C/C, EX12(a)+62G/G, EX14(a) 1359T/T or SNP vidual has poor prognosis and that the tumor cells are EX14(a)483A/A. invasive. Specifically, the individual has an intermediate 0628 Thus, if the tumor or cancerous growth is homozy level of risk of cancer metastasis. That is, the risk is greater gous with the AMFR genotype EX4(a)+14T/T or EX12(a)+ than a person having a homozygous AMFR genotype of 62A/A or EX14(a)1359C/C or EX14(a)483G/G, then it can EX4(a)+14T/T or EX12(a)+62A/A or EX14(a) 1359C/C or be reasonably predicted that the tumor or cancerous growth EX14(a)483G/G, but is lower than a person having a within the patient has a low metastatic potential, that the homozygous genotype of EX4(a)+14C/C, EX12(a)+62G/G, patient has a good prognosis, and that their tumor's cells are EX 14(a) 1359T/T or SNP EX14(a)483A/A. not likely to be highly invasive. That is, the patient does not 0625 Thus, if the individual is homozygous with the have an increased likelihood or increased risk of cancer AMFR genotype EX4(a)+14T/T or EX12(a)+62A/A or metastasis. Similarly, if the tumor or cancerous growth is EX14(a) 1359C/C or EX14(a)483G/G, then it can be reason homozygous with a genotype at an AMFR locus that is in the ably predicted that the tumor in the individual has low same haplotype with the SNPs EX4(a)+14T, EX12(a)+62A metastasis potential, that the cancer has good prognosis and and EX14(a) 1359C (in linkage disequilibrium), or in linkage that the tumor cells are not invasive. That is, the individual disequilibrium with the SNP EX14(a)483G, then it can does not have an increased likelihood or increased risk of reasonably be predicted that the tumor or cancerous growth cancer metastasis. Similarly, if the individual is homozygous within the patient has a low metastatic potential, that the with a genotype at a locus that is in the same haplotype with patient has a good prognosis, and that their tumor's cells are US 2007/0O82347 A1 Apr. 12, 2007 79 not likely to be highly invasive. In other words, the patient embodiments, the VEGFR inhibitor is an antibody specifi does not have an increased likelihood or increased risk of cally immunoreactive with VEGF or VEGFR. In one cancer metastasis. example, Such an antibody is bevacizumab (e.g., Avastin R 0629. In yet another aspect of the present invention, a from Genentech, Inc.). method is provided for predicting drug response in a patient 0633) Once the prognosis of a patient’s response to to treatment with inhibitors of VEGFRs. There are many VEGFR inhibitors is made, suitable treatment regimens inhibitors of VEGFR known in the art. For example, beva (e.g., dosage and frequency of administration, and the like) cizumab (Avastin R) from Genentech, Inc.) is a recombinant can be decided based on the predicted responsiveness of the humanized anti-VEGF antibody that inhibits the VEGFR patient. For example, if the AMFR genotyping result Sug functions. Avastino has approved in the US by the FDA for gests a low responsiveness by the patient to VEGFR inhibi treating colon cancer. Other inhibitors of VEGFR include tors, then a higher dosage of VEGFR inhibitors would be tyrosine kinase inhibitors such as SU5416, SU 11248 and desirably to the patient, or it may be simply decided that PTK787. Thus, in accordance with the present invention, the another class of drugs would be more suitable for the patient. AMFR gene of a patient in need of treatment with a VEGFR Thus, in another aspect of the invention, a method is inhibitor is genotyped to determine the genotype at one or provided for determining a dosage of a VEGFR inhibitor to more of the AMFR loci identified in the present invention, be administered to a patient, comprising determining the namely EX4(a)+14, EX12(a)+62, EX14(a) 1359 and individual’s genotype in the AMFR gene at one or more of EX14(a)483, or another locus at which a genotype is in the loci identified in the present invention, namely EX4(a)+ linkage disequilibrium with one of the SNPs or haplotypes 14, EX12(a)+62, EX14(a) 1359 and EX14(a)483, or another of the present invention. Thus, if one or more the AMFR locus at which the genotype is in linkage disequilibrium with SNPs EX4Q)+14C, EX12(a)+62G, EX14(a) 1359T and SNP one of the SNPs or haplotypes of the present invention to EX14(a)483A are detected, or a SNP that is in linkage determine the likely responsiveness of the patient, and disequilibrium with any one of such SNPs is detected in the determining accordingly the dosage of a VEGFR inhibitor to individual, then it can be reasonably predicted that the be administered to the patient, wherein the presence of one individual is likely to respond to treatment with an inhibitor or more of the AMFR SNPs EX4(a)+14C, EX12(a)+62G, of VEGFR. In other words, once an inhibitor of VEGFR is EX14(a) 1359T and EX14(a)483A, or a SNP that is in linkage administered, there is an increased likelihood that the inhibi disequilibrium with any one of such SNPs would indicate tor will cause positive effect in the individual, including, that the patient is likely to respond to said VEGFR inhibitor e.g., shrinkage or elimination of tumor, increased death of at a lower dosage than another patient without the nucleotide tumor cells, etc. variants. In one embodiment, the method is used in treating 0630 Particularly, if an individual is homozygous with colon cancer. In other embodiments, the method is used in the AMFR genotype EX4(a)+14C/C, EX12(a)+62G/G, treating breast cancer, melanoma, ovarian cancer, brain EX14(a) 1359T/T or SNP EX14(a)483A/A, then the indi cancer, neuroblastoma, uterine cancer, leukemia, lymphoma, vidual has a substantially increased likelihood of being head and neck cancer, thyroid cancer, gastrointestinal can responsive to treatment with a VEGFR inhibitor. If an cer, pancreatic cancer, liver cancer, etc. In preferred embodi individual is heterozygous with the AMFR genotype ments, the VEGFR inhibitor is an antibody specific to VEGF EX4(a)+14T/C, EX12(a)+62A/G, EX14(a) 1359C/T or SNP Or VEGFR. EX14(a)483G/A, then the individual is still likely to respond 0634. In another aspect of the invention, a method is to a VEGFR inhibitor. Specifically, the individual has an provided for selecting an anti-cancer treatment for a patient, intermediate level of responsiveness to VEGFR inhibitors. which comprises determining, in an AMFR gene in a sample That is, the degree of responsiveness is likely to be greater isolated from the patient, the presence or absence of a than that in a person having a homozygous AMFR genotype nucleotide variant that is selected from the group consisting of EX4(a)+14T/T or EX12(a)+62A/A or EX14(a)1359C/C or of EX4(a)+14C, EX12(a)+62G, EX14(a) 1359T and EX14(a)483G/G, but is lower than a person having a EX14(a)483A, or a SNP that is in linkage disequilibrium homozygous genotype of EX4(a)+14C/C, EX12(a)+62G/G, with any one of such SNPs, wherein the presence of said EX 14(a) 1359T/T or SNP EX14(a)483A/A. nucleotide variant would indicate that the patient is likely to 06.31 Thus, if the individual is homozygous with the respond to a VEGFR inhibitor. Thus, if the AMFR genes in AMFR genotype EX4(a)+14T/T or EX12(a)+62A/A or a patient contain one or more of the nucleotide variants of EX14(a) 1359C/C or EX14(a)483G/G, then it can be reason the present invention, then physicians or other decision ably predicted that there is an increased likelihood that the makers may decide based on the genotyping result that it individual exhibits a low responsiveness to treatment with a would be desirable to treat the patient with VEGFR inhibi VEGFR inhibitor. Similarly, if an individual is homozygous tors, particularly antibodies specifically immunoreactive with a genotype at a locus that is in the same haplotype with with VEGF or VEGFR, e.g., bevacizumab (e.g., Avastin R the SNPs EX4(a)+14T, EX12(a)+62A and EX14(a) 1359C (in from Genentech, Inc.). In one embodiment, the selection of linkage disequilibrium), or in the same haplotype (linkage treatment with a VEGFR inhibitor is based on the presence disequilibrium) with the SNP EX14(a)483G, then it can of a homozygous genotype of one or more of the above reasonably be predicted that there is an increased likelihood SNPs. In one embodiment, the method is used in selecting that the individual has a low responsiveness to treatment a treatment of colon cancer. In other embodiments, the with a VEGFR. method is used in selecting a treatment of NSCLCs, breast cancer, melanoma, ovarian cancer, thyoma, brain cancer, 0632. In specific embodiments, the individual in need of neuroblastoma, uterine cancer, leukemia, lymphoma, head VEGFR inhibitor treatment is diagnosed as having cancer, and neck cancer, thyroid cancer, gastrointestinal cancer, e.g., colorectal cancer or ovarian cancer. Also, in certain pancreatic cancer, liver cancer, etc. US 2007/0O82347 A1 Apr. 12, 2007

0635. In yet another aspect of the present invention, a IRF5 or AMFR protein variants (drug target) can be pre method is provided for selecting candidate human Subjects pared by any Suitable methods, e.g., by recombinant expres for participation in a clinical trial involving a VEGFR sion and purification. The polypeptide or fragment thereof inhibitor, which comprises (1) determining, in the AMFR may be free in solution but preferably is immobilized on a gene of an individual, the presence or absence of a nucle Solid Support, e.g., in a protein microchip, or on a cell otide variant that is selected from the group consisting of Surface. Various techniques for immobilizing proteins on a EX4(a)+14C, EX12(a)+62G, EX14(a) 1359T and solid support are known in the art. For example, PCT EX14(a)483A, or a SNP that is in linkage disequilibrium Publication WO 84/03564 discloses synthesizing a large with any one of such SNPs, wherein the presence of said numbers of Small peptide test compounds on a solid Sub nucleotide variant would indicate that the patient is likely to strate. Such as plastic pins or other Surfaces. Alternatively, respond to a VEGFR inhibitor; and (2) deciding whether to purified mutant TLK1, WARS2, ARTS2, MSR, AKAP9, include said individual in the clinical trial. For example, if DNAJD1, GOLPH4, RABEP1, TAP2, NARG2, DDX58, the patient has one or more of the nucleotide variants, then CD39, FKBP1a, SRI, XRRA1, IRF5 or AMFR protein or clinical trial for a VEGFR inhibitor may include that patient, fragment thereof can be coated directly onto plates Such as particularly when the patient is homozygous in one or more multi-well plates. Non-neutralizing antibodies, i.e., antibod of the SNPs. In one embodiment, the method is used in a ies capable binding to the TLK1, WARS2, ARTS2, MSR, clinical trial for testing a VEGFR inhibitor in colon cancer. AKAP9, DNAJD1, GOLPH4, RABEP1, TAP2, NARG2, In other embodiments, the method is used in selecting DDX58, CD39, FKBP1a, SRI, XRRA1, IRF5 or AMFR patients for inclusion in clinical trials for testing a VEGFR protein or fragment thereof but do not substantially affect its inhibitor in breast cancer, melanoma, ovarian cancer, brain biological activities may also be used for immobilizing the cancer, neuroblastoma, uterine cancer, leukemia, lymphoma, TLK1, WARS2, ARTS2, MSR, AKAP9, DNAJD1, head and neck cancer, thyroid cancer, gastrointestinal can GOLPH4, RABEP1, TAP2, NARG2, DDX58, CD39, cer, pancreatic cancer, liver cancer, etc. In preferred embodi FKBP1a, SRI, XRRA1, IRF5 or AMFR protein or fragment ments, the VEGFR inhibitor is an antibody specifically thereof on a solid Support. immunoreactive with VEGF or VEGFR. 0639. To effect the screening, test compounds can be 8. Screening Assays contacted with the immobilized TLK1, WARS2, ARTS2, MSR, AKAP9, DNAJD1, GOLPH4, RABEP1, TAP2, 0636. The present invention further provides a method NARG2, DDX58, CD39, FKBP1a, SRI, XRRA1, IRF5 or for identifying compounds for treating or preventing symp AMFR protein or fragment thereof to allow binding to occur toms amendable to treatment by alteration of TLK1, to form complexes under standard binding assays. Either the WARS2, ARTS2, MSR, AKAP9, DNAJD1, GOLPH4, drug target or test compounds are labeled with a detectable RABEP1, TAP2, NARG2, DDX58, CD39, FKBP1a, SRI, marker using well known labeling techniques. To identify XRRA1, IRF5 or AMFR protein activities. For this purpose, binding compounds, one may measure the formation of the variant TLK1, WARS2, ARTS2, MSR, AKAP9, DNAJD1, drug target-test compound complexes or kinetics for the GOLPH4, RABEP1, TAP2, NARG2, DDX58, CD39, formation thereof. FKBP1a, SRI, XRRA1, IRF5 or AMFR protein or fragment 0640 Alternatively, a known ligand capable of binding to thereof containing a particular amino acid variant in accor the drug target can be used in competitive binding assays. dance with the present invention can be used in any of a Complexes between the known ligand and the drug target variety of drug screening techniques. Drug screening can be can be formed and then contacted with test compounds. The performed as described herein or using well known tech ability of a test compound to interfere with the interaction niques, such as those described in U.S. Pat. Nos. 5,800,998 between the drug target and the known ligand is measured and 5,891,628, both of which are incorporated herein by using known techniques. One exemplary ligand is an anti reference. The candidate therapeutic compounds may body capable of specifically binding the drug target. Par include, but are not limited to proteins, Small peptides, ticularly, such an antibody is especially useful for identify nucleic acids, and analogs thereof. Preferably, the com ing peptides that share one or more antigenic determinants pounds are Small organic molecules having a molecular of the TLK1, WARS2, ARTS2, MSR, AKAP9, DNAJD1, weight of no greater than 10,000 dalton, more preferably GOLPH4, RABEP1, TAP2, NARG2, DDX58, CD39, less than 5,000 dalton. FKBP1a, SRI, XRRA1, IRF5 or AMFR protein or fragment 0637. In one embodiment of the present invention, the thereof. method is primarily based on binding affinities to screen for 0641. In another embodiment, a yeast two-hybrid system compounds capable of interacting with or binding to a may be employed to Screen for proteins or Small peptides TLK1, WARS2, ARTS2, MSR, AKAP9, DNAJD1, capable of interacting with a TLK1, WARS2, ARTS2, MSR, GOLPH4, RABEP1, TAP2, NARG2, DDX58, CD39, AKAP9, DNAJD1, GOLPH4, RABEP1, TAP2, NARG2, FKBP1a, SRI, XRRA1, IRF5 or AMFR protein containing DDX58, CD39, FKBP1a, SRI, XRRA1, IRF5 or AMFR one or more amino acid variants. Compounds to be screened protein variant. For example, a battery of fusion proteins may be peptides or derivatives or mimetics thereof, or each contains a random Small peptide fused to e.g., Gal 4 non-peptide Small molecules. Conveniently, commercially activation domain, can be co-expressed in yeast cells with a available combinatorial libraries of compounds or phage fusion protein having the Gal 4 binding domain fused to a display libraries displaying random peptides are used. TLK1, WARS2, ARTS2, MSR, AKAP9, DNAJD1, 0638 Various screening techniques known in the art may GOLPH4, RABEP1, TAP2, NARG2, DDX58, CD39, be used in the present invention. The TLK1, WARS2, FKBP1a, SRI, XRRA1, IRF5 or AMFR protein variant. In ARTS2, MSR, AKAP9, DNAJD1, GOLPH4, RABEP1, this manner, Small peptides capable of interacting with the TAP2, NARG2, DDX58, CD39, FKBP1a, SRI, XRRA1, TLK1, WARS2, ARTS2, MSR, AKAP9, DNAJD1, US 2007/0O82347 A1 Apr. 12, 2007

GOLPH4, RABEP1, TAP2, NARG2, DDX58, CD39, protein are revealed. Medicinal chemists can then design FKBP1a, SRI, XRRA1, IRF5 or AMFR protein variant can analog compounds having similar moieties and structures. In be identified. Alternatively, compounds can also be tested in addition, the three-dimensional structure of wild-type a yeast two-hybrid system to determine their ability to TLK1, WARS2, ARTS2, MSR, AKAP9, DNAJD1, inhibit the interaction between the TLK1, WARS2, ARTS2, GOLPH4, RABEP1, TAP2, NARG2, DDX58, CD39, MSR, AKAP9, DNAJD1, GOLPH4, RABEP1, TAP2, FKBP1a, SRI, XRRA1, IRF5 or AMFR protein is also NARG2, DDX58, CD39, FKBP1a, SRI, XRRA1, IRF5 or desirably deciphered and compared to that of a variant AMFR protein variant and a known protein capable of TLK1, WARS2, ARTS2, MSR, AKAP9, DNAJD1, interacting with the TLK1, WARS2, ARTS2, MSR, AKAP9, GOLPH4, RABEP1, TAP2, NARG2, DDX58, CD39, DNAJD1, GOLPH4, RABEP1, TAP2, NARG2, DDX58, FKBP1a, SRI, XRRA1, IRF5 or AMFR protein. This will CD39, FKBP1a, SRI, XRRA1, IRF5 or AMFR protein or aid in designing compounds selectively interacting with the polypeptide or fragment thereof. Again, one example of Such variant TLK1, WARS2, ARTS2, MSR, AKAP9, DNAJD1, proteins is an antibody specifically against the TLK1. GOLPH4, RABEP1, TAP2, NARG2, DDX58, CD39, WARS2, ARTS2, MSR, AKAP9, DNAJD1, GOLPH4, FKBP1a, SRI, XRRA1, IRF5 or AMFR protein. RABEP1, TAP2, NARG2, DDX58, CD39, FKBP1a, SRI, 0.645. In another approach, a selected peptide compound XRRA1, IRF5 or AMFR protein variant. Yeast two-hybrid capable of binding the TLK1, WARS2, ARTS2, MSR, systems and use thereof are generally known in the art and AKAP9, DNAJD1, GOLPH4, RABEP1, TAP2, NARG2, are disclosed in, e.g., Bartel et al., in: Cellular Interactions DDX58, CD39, FKBP1a, SRI, XRRA1, IRF5 or AMFR in Development: A Practical Approach, Oxford University protein variant can be analyzed by an alanine Scan. See Press, pp. 153-179 (1993); Fields and Song, Nature, Wells, et al., Methods Enzymol., 202:301-306 (1991). In this 340:245–246 (1989); Chevray and Nathans, Proc. Natl. technique, an amino acid residue of the peptide is replaced Acad. Sci. USA, 89:5789-5793 (1992); Lee et al., Science, by Alanine, and its effect on the peptide's binding affinity to 268: 836-844 (1995); and U.S. Pat. Nos. 6,057,101, 6,051, the variant TLK1, WARS2, ARTS2, MSR, AKAP9, 381, and 5,525.490, all of which are incorporated herein by DNAJD1, GOLPH4, RABEP1, TAP2, NARG2, DDX58, reference. CD39, FKBP1a, SRI, XRRA1, IRF5 or AMFR protein is 0642. The compounds thus identified can be further tested. Amino acid residues of the selected peptide are tested for activities, e.g., in stimulating the niological activi analyzed in this manner to determine the domains or resi ties of the variant TLK1, WARS2, ARTS2, MSR, AKAP9, dues of the peptide important to its binding to variant TLK1, DNAJD1, GOLPH4, RABEP1, TAP2, NARG2, DDX58, WARS2, ARTS2, MSR, AKAP9, DNAJD1, GOLPH4, CD39, FKBP1a, SRI or XRRA1, e.g., in DNA mismatch RABEP1, TAP2, NARG2, DDX58, CD39, FKBP1a, SRI, repair. XRRA1, IRF5 or AMFR protein. These residues or domains 0643. Once an effective compound is identified, struc constituting the active region of the compound are known as tural analogs or mimetics thereof can be produced based on its “pharmacophore.” This information can be very helpful rational drug design with the aim of improving drug efficacy in rationally designing improved compounds. and stability, and reducing side effects. Methods known in 0.646. Once the pharmacophore has been elucidated, a the art for rational drug design can be used in the present structural model can be established by a modeling process invention. See, e.g., Hodgson et al., Bio/Technology, 9:19-21 which may include analyzing the physical properties of the (1991); U.S. Pat. Nos. 5,800,998 and 5,891,628, all of which pharmacophore such as Stereochemistry, charge, bonding, are incorporated herein by reference. An example of rational and size using data from a range of sources, e.g., NMR drug design is the development of HIV protease inhibitors. analysis, X-ray diffraction data, alanine Scanning, and spec See Erickson et al., Science, 249:527-533 (1990). Prefer troscopic techniques and the like. Various techniques includ ably, rational drug design is based on one or more com ing computational analysis, similarity mapping and the like pounds selectively binding to a variant TLK1, WARS2, can all be used in this modeling process. See e.g., Perry et ARTS2, MSR, AKAP9, DNAJD1, GOLPH4, RABEP1, al., in OSAR. Quantitative Structure-Activity Relationships TAP2, NARG2, DDX58, CD39, FKBP1a, SRI, XRRA1, in Drug Design, pp. 189-193, Alan R. Liss, Inc., 1989; IRF5 or AMFR protein or a fragment thereof. Rotivinen et al., Acta Pharmaceutical Fennica, 97:159-166 (1988); Lewis et al., Proc. R. Soc. Lond, 236:125-140 0644. In one embodiment, the three-dimensional struc (1989); McKinally et al., Annu. Rev. Pharmacol. Toxiciol., ture of, e.g., a TLK1, WARS2, ARTS2, MSR, AKAP9, 29:111-122 (1989). Commercial molecular modeling sys DNAJD1, GOLPH4, RABEP1, TAP2, NARG2, DDX58, tems available from Polygen Corporation, Waltham, Mass. CD39, FKBP1a, SRI, XRRA1, IRF5 or AMFR protein include the CHARMm program, which performs the energy variant, is determined by biophysics techniques such as minimization and molecular dynamics functions, and X-ray crystallography, computer modeling, or both. Desir QUANTA program which performs the construction, ably, the structure of the complex between an effective graphic modeling and analysis of molecular structure. Such compound and the variant TLK1, WARS2, ARTS2, MSR, programs allow interactive construction, visualization and AKAP9, DNAJD1, GOLPH4, RABEP1, TAP2, NARG2, modification of molecules. Other computer modeling pro DDX58, CD39, FKBP1a, SRI, XRRA1, IRF5 or AMFR protein is determined, and the structural relationship grams are also available from BioDesign, Inc. (Pasadena, between the compound and the protein is elucidated. In this Calif.), Hypercube, Inc. (Cambridge, Ontario), and Allelix, manner, the moieties and the three-dimensional structure of Inc. (Mississauga, Ontario, Canada). the selected compound, i.e., lead compound, critical to the 0647. A template can be formed based on the established its binding to the variant TLK1, WARS2, ARTS2, MSR, model. Various compounds can then be designed by linking AKAP9, DNAJD1, GOLPH4, RABEP1, TAP2, NARG2, various chemical groups or moieties to the template. Various DDX58, CD39, FKBP1a, SRI, XRRA1, IRF5 or AMFR moieties of the template can also be replaced. In addition, in US 2007/0O82347 A1 Apr. 12, 2007 case of a peptide lead compound, the peptide or mimetics 2.5x10 or less. The ARTS1 mRNA expression level was thereof can be cyclized, e.g., by linking the N-terminus and identified to be inheritable at a LOD score of greater than C-terminus together, to increase its stability. These rationally 9.7. The MSR mRNA expression level was identified to be designed compounds are further tested. In this manner, inheritable at a LOD score of greater than 4.3. SNP probes pharmacologically acceptable and stable compounds with in the MSR gene region were also associated with the improved efficacy and reduced side effect can be developed. mRNA expression levels atap value of 0.00634 or less. SNP probes in the AKAP9 gene region were also associated with EXAMPLE 1. the mRNA expression levels at a p value of 1.35e-08 or less. SNP probes in the DNAJD1 gene region were associated Generation of Expression and SNP Genotyping with the mRNA expression levels at a p value of 3.76x107 Data or less. The GOLPH4 mRNA expression level was identified 0648 Human lymphoblastoid cell lines were purchased to be inheritable at a LOD score of greater than 7.9. The from Coriell (Camden, N.J.). Cell lines were grown in RABEP1 mRNA expression level was identified to be RPMI1640 media containing 15% heat inactivated FBS, 2 inheritable at a LOD score of greater than 9.2. SNP probes mM L-glutamine and 1x antibiotic antimycotic to a density in the RABEP1 gene region were also associated with the of 5x10. Then fresh media was added and the cells were mRNA expression levels at ap value of 6.6x10 or less. The TAP2 mRNA expression level was identified to be inherit harvested 24 hours later. Total number of cells harvested for able at a LOD score of greater than 4.2. SNP probes in the RNA isolation is approximately 10x10, and for DNA is NARG2 gene region were also associated with the mRNA approximately 5x10'. RNA was prepared using the expression levels at a p value of 3.6x107 or less. The TAP2 Ribopure kit provided by Ambion, Inc. DNA was isolated mRNA expression level was identified to be inheritable at a using a DNeasy Tissue kit from Qiagen. LOD score of greater than 4.2. SNP probes in the NARG2 0649) RNA was converted to labeled cRNA using the gene region were also associated with the mRNA expression protocol recommended by Affymetrix, Inc. High density levels at a p value of 3.6x107 or less. The DDX58 mRNA Hu133A expression chips from Affymetrix were hybridized expression level was identified to be inheritable at a LOD to the cFNA, washed, stained and scanned using the rec score of greater than 5.8. The CD39 mRNA expression level ommended protocols. was identified to be inheritable at a LOD score of greater than 1.39. SNP probes in the CD39 gene region were also 0650 DNA template for the Centurion SNP chip was associated with the mRNA expression levels at a p value of generated using the protocol recommended by Affymetrix 2.4x10 or less. The FKBP1a mRNA expression level was Inc. Centurion SNP chips from Affymetrix were hybridized identified to be inheritable at a LOD score of greater than to the DNA template, washed, stained and Scanned using the 5.3. SNP probes in the FKBP1a gene region were also recommended protocols. associated with the mRNA expression levels at a p value of 31.9x10 or less. The SRI mRNA expression level was EXAMPLE 2 identified to be inheritable at a LOD score of greater than 2.86. SNP probes in the SRI gene region were also associ Linkage and Association Analysis of Expression ated with the mRNA expression levels at a p value of and SNP Genotyping Data 5.7x10 or less. The XRRA1 mRNA expression level was 0651 mRNA expression data was extracted using RMA identified to be inheritable at a LOD score of greater than (robust multi-array average) as the Summary measure for 3.8. SNP probes in the XRRA1 gene region were also Affymetrix oligonucleotide array data. See Irizarry et al., associated with the mRNA expression levels at a p value of Biostatistics, 4(2):249-264 (2003). RMA values were nor 4.0x10 or less. malized by Subtracting means for each sex. Association analysis between Affy SNP genotypes and mRNA levels was EXAMPLE 3 done by a standard statistical test. A subset of 10,000 SNPs from Afly 120K SNP chip was used for linkage analysis. See Variant Discovery Thomas et al., Statistics and Computing, 10:259-269 (2000). MCLINK program was used to define inheritance at the 0653) To identify sequence variants that serve as diag subset of 10,000 SNPs. A blocked Gibbs sampler was used nostics for predicting RNA levels, variant discovery was to fit finite normal mixtures to sex-corrected RMA data. carried out on all exons of the TLK1, WARS2, ARTS2, These normal mixtures were used to create a linkage model MSR, AKAP9, DNAJD1, GOLPH4, RABEP1, TAP2, where mRNA levels were treated as QTL, phenotypes. See NARG2, DDX58, CD39, FKBP1a, SRI, XRRA1, IRF5 or Ishwaran and James, J. Comp. Graph. Statist., 11(3):1-26 AMFR gene and 1 kb of upstream regulatory sequence. The ((2002). Robust multipoint Lod scores for each mRNA level 30 parent individuals of the 15 families used in RNA were calculated at all 10,000 SNP locations. See Abkevich profiling represent the genomic variability of the entire et al., Genetic Epidemiology, 21 (Suppl 1):S492-497 (2001). sample set and were therefore selected for variant detection. Heritability estimation is done by MERLIN software. See 0654 For each exon and 1000 bases upstream of exon 1 Abecasis et al., Nat. Genet., 30:97-101 (2002). two pairs of nested primers were designed using proprietary 0652) The TLK1 mRNA expression level was identified software. The nested primer pair was tailed with universal to be inheritable at a LOD score of greater than 5.6. SNP M13 primers. Primers were positioned to include a mini probes in the TLK1 gene region were also associated with mum of 30 bases of intronic sequence at either end of an the mRNA expression levels at a p value of 1.5x10" or exon in the final PCR product. This allows for examination less. SNP probes in the WARS2 gene region were also of exon/intron boundaries. Large exons and continuous associated with the mRNA expression levels at a p value of promoter sequence was amplified with overlapping primers US 2007/0O82347 A1 Apr. 12, 2007 sets. All amplicons were amplified using a robotic system haplotypes. Frequencies of each haplotype are calculated. and standard PCR conditions. PCR products were treated LD nucleotide variants are therefore identified based on such with shrimp alkaline phosphatase to remove free nucleotides frequencies. and Submitted to dye-primer sequencing using forward and reverse M13 sequencing primers. Products were separated 0660 LD SNPs can be extrapolated using the “Single on capillary sequencing machines (MegaBACE) and base Nucleotide Polymorphism dbSNP search” tool, which is called using proprietary Software. Detection of variants was available from the National Center for Biotechnology Infor performed by computer software that compares individual mation, U.S. National Library of Medicine (Bethesda, Md., base-called sequence traces to a reference sequence. U.S.A.). as of the priority date or filing date. This can be done in accordance with the methods describes in this 0655 Tables 36-80 show the association of the different Example and in Example 4. Representative LDSNPs are SNPs and haplotypes with TLK1, WARS2, ARTS2, MSR, shown in Table 81. AKAP9, DNAJD1, GOLPH4, RABEP1, TAP2, NARG2, DDX58, CD39, FKBP1a, SRI, XRRA1, IRF5 or AMFR 0661. It is noted that the nucleotide sequences surround gene expression levels. For T-statistic calculation, a standard ing each of the SNPs are provided in Sequence Listing and two-sample t-test assuming equal variances was performed as indicated in Tables 1-35. While there may be alternatively to compare the mean expression values for individuals who spliced variants of gene transcripts and the chromosome carry a certain genotype and those who do not. The table locations may change over time, the exon and intron num gives the t-statistic and the p-value for a one-sided hypoth bering and the SNP positions of the present invention would esis test. be clearly understood by a skilled artisan by reference to the sequences in the sequence listing together with GenBank EXAMPLE 4 Accession Numbers or a variant or modification of this GenBank sequence. However, it is noted that the SNPs or Discovery of Additional SNPs in Linkage nucleotide variants of the present invention are by no means Disequilibrium with the SNPs Associated with limited to be only in the context of the sequences in the mRNA Levels sequence listings or the particular GenBank entry referred to 0656. After the initial identification of the association of herein. Rather, it is recognized that GenBank sequences may an mRNA level-associated SNP, a search for additional contain unrecognized sequence errors only to be corrected at SNPs (or nucleotide variants) in linkage disequilibrium (LD) a later date, and additional gene variants may be discovered with the mRNA level-associated SNP (or nucleotide variant) in the future. The present invention encompasses SNPs or is undertaken. For this purpose, the available LD data for the nucleotide variants as referred to in Tables 1-35 irrespective relevant chromosome of the CEU population of HapMap of Such sequence contexts. Indeed, even if the GenBank phase II can be downloaded and queried. entries or chromosome locations referred to herein are changed based on either error corrections or additional 0657 Parameters for the query are set to reveal other variants discovered, skilled artisans apprised of the present SNPs in LD with the mRNA level-associated SNP (or disclosure would still be able to determine or analyze the nucleotide variant) with r values 20.8. The query identifies SNPs or haplotypes of the present invention in the new additional LD SNPs. sequence contexts. 0658) HapMap SNPs with r values 20.8 are culled from 0662 All publications and patent applications mentioned the query if their distance from the seed SNP is too great, in the specification are indicative of the level of those skilled i.e., >100 kbp, or if the LD appears to have arisen by chance. in the art to which this invention pertains. All publications EXAMPLE 5 and patent applications are herein incorporated by reference to the same extent as if each individual publication or patent Identification of Alleles in Linkage Disequilibrium application was specifically and individually indicated to be with the mRNA Level-Associated Allele incorporated by reference. 0659. To determine which alleles at LDSNPs are in LD 0663 Although the foregoing invention has been with the mRNA level-associated nucleotide variant, geno described in some detail by way of illustration and example type calls for mRNA level-associated SNP and the identified for purposes of clarity of understanding, it will be obvious LD SNPs from 90 individuals within the CEU population that certain changes and modifications may be practiced can be downloaded from HapMap and used to construct within the scope of the appended claims.

SEQUENCE LISTING The patent application contains a lengthy “Sequence Listing section. A copy of the “Sequence Listing is available in electronic form from the USPTO web site (http://seqdata.uspto.gov/?pageRequest=docDetail&DocID=US20070082347A1). An electronic copy of the “Sequence Listing will also be available from the USPTO upon request and payment of the fee set forth in 37 CFR 1.19(b)(3). US 2007/0O82347 A1 Apr. 12, 2007

What is claimed is: EX9(a)+18T, EX11(a)59A, EX12(a)-28T, EX12(a)-7A, 1. An isolated nucleic acid or the complement thereof, EX 15(a)88C, EX19(a) 173C, EX 19(a)328m, said isolated nucleic acid comprising a contiguous span of at EX 19(a)885T, EX20(a).2105C, EX20(a)719C and least 18 nucleotide residues of: EX20(a) 1038A: (a) an ARTS nucleic acid, at least one of said residues (d) said gene is MSR and said nucleotide variant is chosen being a nucleotide variant of EX1(a)-1125 or from the group of EX1(a)-674T, EX1(a) 19T. EX1(a)+ EX12(a)44; 129m, EX5(a) 123C, EX5(a) 136T, EX7(a) 146A, EX10(a)+83A, EX11(a)+54T, EX14(a) 14C, (b) a DNAJD1 nucleic acid, at least one of said residues EX14(a) 106G, EX14(a) 142A and EX15(a)686G, and being a nucleotide variant of EX5(a)+72; and LD SNPs thereof. (c) a RABEP1 nucleic acid, at least one of said residues 5. A method of predicting the pathological, pharmaco being a nucleotide variant of EX1(a)-551, EX18(a)646 logical or pharmacokinetic characteristic of a human Sub or EX18(a)690. ject, comprising: 2. A DNA microchip comprising one or more said isolated determining the genotype at a loci of in Tables 1-35 and nucleic acid according to claim 1. Table 81, said genotype is associated with a specific 3. A method of genotyping a human individual, compris gene expression phenotype; and ing detecting, or determining the presence or absence of a nucleotide variant of claim 1 in said individual. predicting a pathological, pharmacological or pharmaco 4. A method of predicting the expression of a gene in a kinetic characteristic of a human Subject according to human Subject, comprising determining the presence or said specific gene expression phenotype. absence of a nucleotide variant associated with high gene 6. The method of claim 5, wherein the TLK1 gene is expression phenotype, wherein: genotyped, and where the presence of one or more of the SNPs EX7(a)--63G, EX7(a)--190T, EX 11(a)51A, (a) said gene is TLK1 and said nucleotide variant is EX25(a)855G and LDSNPs thereof would indicate that the chosen from the group of EX7(a)+63G, EX7(a)+190T, individual has an increased Susceptibility to diseases asso EX 11(a)51A, EX25(a)855G and an LDSNP thereof; ciated with DNA damage including cancer. (b) said gene is WARS2 and said nucleotide variant is 7. The method of claim 5, wherein WARS2 gene is chosen from the group of EX1(a)-963 A, EX1(a)-103C, genotyped and wherein the presence of one or more of EX6(a)780A, EX6(a842G and EX6(a)2152A, and LD EX1(a)-963 A, EX1(a)-103C, EX6(a)780A, EX6(a)842G and SNPs thereof; EX6(a)2152A, and LDSNPs thereof would indicate that the human Subject has an increased likelihood of developing (c) said gene is ARTS1 and said nucleotide variant is cardiovascular disease, cancer or neurodegenerative disease, chosen from the group of EX1(a)-1125T, EX2(a)397G, or has a poor prognosis of Such a disease. EX20(a) 1085A, EX6(a)126A, EX 12(a)44G, EX 15(a)74G, EX6(a)149T, EX8(a)-10A, EX9(a)39T. k k k k k