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US 2012/0010274 A1 BEGOVICH Et Al US 201200 10274A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2012/0010274 A1 BEGOVICH et al. (43) Pub. Date: Jan. 12, 2012 (54) GENETIC POLYMORPHSMS ASSOCATED Publication Classification WITH PSORIASIS, METHODS OF (51) Int. Cl. DETECTION AND USES THEREOF A63L/7088 (2006.01) (75) Inventors: Ann BEGOVICH, El Cerrito, CA C40B 30/00 (2006.01) (US); Ellen BEASLEY, CI2O I/68 (2006.01) Burlingame, CA (US); Michele GOIN 33/53 (2006.01) CARGILL, Orinda, CA (US); GOIN 33/566 (2006.01) Steven SCHRODI, Livermore, CA (52) U.S. Cl. ...................... 514/44 R; 436/501; 435/6.11; (US) 506/7 (73) Assignee: CELERA CORPORATION, Alameda, CA (US) (57) ABSTRACT (21) Appl. No.: 13/175,159 The present invention is based on the discovery of genetic polymorphisms that are associated with psoriasis and related (22) Filed: Jul. 1, 2011 pathologies. In particular, the present invention relates to nucleic acid molecules containing the polymorphisms, Related U.S. Application Data including groups of nucleic acid molecules that may be used as a signature marker set, such as a haplotype, a diplotype, (62) Division of application No. 1 1/899.017, filed on Aug. variant proteins encoded by Such nucleic acid molecules, 31, 2007, now Pat. No. 7,993,833. reagents for detecting the polymorphic nucleic acid mol (60) Provisional application No. 60/928,625, filed on May ecules and proteins, and methods of using the nucleic acid and 9, 2007, provisional application No. 60/844,100, filed proteins as well as methods of using reagents for their detec on Sep. 11, 2006. tion. US 2012/0010274 A1 Jan. 12, 2012 GENETIC POLYMORPHISMIS ASSOCATED locus in the MHC region on 6p21 (PSORS1 MIM 177900), WITH PSORIASIS, METHODS OF but have not yielded consistent evidence for other regions. DETECTION AND USES THEREOF 0005 Linkage and association in the MHC (6p21) are thought to be due to HLA-C, in particular psoriasis Suscepti CROSS-REFERENCE TO RELATED bility effects are thought to be caused by the *0602 allele", APPLICATIONS although other candidate genes in the area may also contrib 0001. This application is a divisional application of U.S. ute to disease predisposition. Association studies have iden non-provisional application Ser. No. 1 1/899,017, filed Aug. tified three genes under linkage peaks, with considerable 31, 2007, which claims priority to U.S. provisional applica evidence for linkage disequilibrium with psoriasis, namely tion Ser. No. 60/928,625, filed on May 9, 2007, and to U.S. SLC9A3R1/NAT9 and RAPTOR (KIAA1303) in 17q25, and provisional application Ser. No. 60/844,100, filed on Sep. 11, SLC12A8 in 3q21. Several other genes including VDR, 2006, the contents each of which are hereby incorporated by MMP2, IL10, IL1RN, IL12B, and IRF2 (Genetic Association reference in their entirety into this application. Database, OMIM) have been associated with psoriasis in sample sets of varying sizes and of different ethnicities; how FIELD OF THE INVENTION ever, without more data from additional independent studies, 0002 The present invention is in the field of diagnosis and it is difficult to draw statistically sound conclusions about therapy of psoriasis. In particular, the present invention whether these markers are truly associated with disease. relates to specific single nucleotide polymorphisms (SNPs) in Thus, there remains a need for the discovery of reliable mark the human genome, and their association with psoriasis and ers that can associate themselves with psoriasis, and in turn, related pathologies. Based on differences in allele frequen would facilitate the diagnosis and treatment of the disease. cies in the psoriasis patient population relative to normal The discovery of genetic markers which are useful in identi individuals, the naturally-occurring SNPs disclosed herein fying psoriasis individuals who are at increased risk for devel can be used as targets for the design of diagnostic reagents oping psoriasis may lead to, for example, better therapeutic and the development of therapeutic agents, as well as for disease association and linkage analysis. In particular, the strategies, economic models, and health care policy deci SNPs of the present invention are useful for identifying an S1O.S. individual who is at an increased or decreased risk of devel 0006 SNPs oping psoriasis and for early detection of the disease, for 0007. The genomes of all organisms undergo spontaneous providing clinically important information for the prevention mutation in the course of their continuing evolution, generat and/or treatment of psoriasis, and for screening and selecting ing variant forms of progenitor genetic sequences (Gusella, therapeutic agents. The SNPs disclosed herein are also useful Ann. Rev. Biochem. 55,831-854 (1986)). A variant form may for human identification applications. Methods, assays, kits, confer an evolutionary advantage or disadvantage relative to and reagents for detecting the presence of these polymor a progenitor form or may be neutral. In some instances, a phisms and their encoded products are provided. variant form confers an evolutionary advantage to the species and is eventually incorporated into the DNA of many or most BACKGROUND OF THE INVENTION members of the species and effectively becomes the progeni 0003 Psoriasis is a common, chronic, T-cell-mediated tor form. Additionally, the effects of a variant form may be inflammatory disease of the skin affecting -2-3% of whites of both beneficial and detrimental, depending on the circum European descent. Although this disease is found in all popu stances. For example, a heterozygous sickle cell mutation lations, its prevalence is lower in Asians and African-Ameri confers resistance to malaria, but a homozygous sickle cell cans and also declines at lower latitudes.' The most common mutation is usually lethal. In many cases, both progenitor and form, psoriasis Vulgaris, is characterized by varying numbers variant forms survive and co-exist in a species population. of red, raised, scaly skin patches that can be present on any The coexistence of multiple forms of a genetic sequence gives body Surface, but most often appear on the elbows, knees and rise to genetic polymorphisms, including SNPs. scalp. The onset of disease usually occurs early in life (15-30 0008. Approximately 90% of all polymorphisms in the years) and affects males and females equally. Up to 30% of human genome are SNPs. SNPs are single base positions in individuals with psoriasis will develop an inflammatory DNA at which different alleles, or alternative nucleotides, arthritis, which can affect the peripheral joints of the hands exist in a population. The SNP position (interchangeably and feet, large joints, or the central axial-skeleton.’ Patho referred to herein as SNP, SNP site, SNP locus, SNP marker, logically, psoriasis is characterized by vascular changes, or marker) is usually preceded by and followed by highly hyperproliferation of keratinocytes, altered epidermal differ conserved sequences of the allele (e.g., sequences that vary in entiation and inflammation. In particular, the reaction of less than /100 or /1000 members of the populations). An indi cells in the epidermis to type 1 effector molecules produced vidual may be homozygous or heterozygous for an allele at by T-cells results in the characteristic pathology of the each SNP position. A SNP can, in some instances, be referred plaques. to as a “cSNP to denote that the nucleotide sequence con 0004. The genetics of psoriasis are complex and highly taining the SNP is an amino acid coding sequence. heritable as evidenced by an increased rate of concordance in 0009. A SNP may arise from a substitution of one nucle monozygotic twins over dizygotic twins (35%-72% vs. otide for another at the polymorphic site. Substitutions can be 12-23%) and a substantially increased incidence in family transitions or transversions. A transition is the replacement of members of affected individuals (first-degree relatives 6%); one purine nucleotide by another purine nucleotide, or one however, it is clear that environmental effects are also respon pyrimidine by another pyrimidine. A transversion is the sible for disease susceptibility. Ten genome-wide linkage replacement of a purine by a pyrimidine, or vice versa. A SNP scans have resulted in strong evidence for a Susceptibility may also be a single base insertion or deletion variant referred US 2012/0010274 A1 Jan. 12, 2012 to as an “indel' (Weber et al., “Human diallelic insertion/ although not causative, are nonetheless also useful for diag deletion polymorphisms’. Am J Hum Genet 2002 October; nostics, disease predisposition screening, and other uses. 71(4):854-62). 0014. An association study of a SNP and a specific disor 0010. A synonymous codon change, or silent mutation/ der involves determining the presence or frequency of the SNP allele in biological samples from individuals with the SNP (terms such as “SNP, “polymorphism”, “mutation”, disorder of interest, Such as psoriasis and related pathologies “mutant”, “variation', and “variant” are used herein inter and comparing the information to that of controls (i.e., indi changeably), is one that does not result in a change of amino viduals who do not have the disorder; controls may be also acid due to the degeneracy of the genetic code. A Substitution referred to as “healthy” or “normal individuals) who are that changes a codon coding for one amino acid to a codon preferably of similar age and race. The appropriate selection coding for a different amino acid (i.e., a non-synonymous of patients and controls is important to the success of SNP codon change) is referred to as a missense mutation. A non association studies. Therefore, a pool of individuals with sense mutation results in a type of non-synonymous codon well-characterized phenotypes is extremely desirable. change in which a stop codon is formed, thereby leading to 0015. A SNP may be screened in diseased tissue samples premature termination of a polypeptide chain and a truncated or any biological sample obtained from a diseased individual, protein.
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