US 20080280955A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2008/0280955A1 McCamish (43) Pub. Date: Nov. 13, 2008

(54) METHODS AND COMPOSITIONS FOR Publication Classification SCREENING AND TREATMENT OF (51) Int. Cl. DSORDERS OF BLOOD GLUCOSE A6II 3/4436 (2006.01) REGULATION CI2O I/68 (2006.01) C7H 2L/04 (2006.01) (75) Inventor: Mark A. McCamish, Cupertino, C07K 2/00 (2006.01) CA (US) (52) U.S. Cl...... 514/342:435/6:536/24.5:530/300 (57) ABSTRACT Correspondence Address: In one aspect, the invention provides a method of Screening PERLEGEN SCIENCES, INC. and, optionally, treatment of an individual Suffering from an LEGAL DEPARTMENT insulin resistance disorder by Screening an individual in need 2021 STERLIN COURT of treatment for an insulin resistance disorder for one or more MOUNTAIN VIEW, CA 94043 (US) genetic variations indicating a predisposition to a response to an insulin sensitizer; and, optionally, administering or not administering an insulin sensitizer to the individual based on (73) Assignee: Perlegen Sciences, Inc., Mountain the results of the screening. The insulin sensitizer for which View, CA (US) the individual is screened and the insulin sensitizer that is administered or not administered may be the same or differ ent. In another aspect, the invention provides methods com (21) Appl. No.: 11/541,495 prising identifying one or more genetic variations, e.g., one or more single nucleotide polymorphisms, that at least partly (22) Filed: Sep. 29, 2006 differentiate between a subset of a plurality of individuals who experience a response when administered an insulin Related U.S. Application Data sensitizer, and a subset of said plurality of individuals who do not experience a response when administered the insulin sen (60) Provisional application No. 60/722,357, filed on Sep. sitizer. The invention also provides nucleic acids, polypep 30, 2005, provisional application No. 60/722,636, tides, antibodies, kits, and business methods associated with filed on Sep. 30, 2005. these screening and association methods.

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INPUT DEVICE HARD DRIVE DATA - GeneticWariation -Phenotype Data (Optional) 1 02 -Response to insulin Sensitizer -/ NDIVIDUAL SUBJECT Patent Application Publication Nov. 13, 2008 Sheet 1 of 2 US 2008/028.0955 A1

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Genotype Responders and Non Responder to Drug A (member of Drug-Class X)

Identify genetic variation that predicts predisposition to a response to Drug A

Genotype Individuals in Clinical Trial for Drug B (member of Drug-Class X)

Predict responders and non responders to Drug B based on genotypes of individuals

Clinical Trial for Drug B using predictor to stratify or enroll

Confirm Responders and Responders to Drug B based on results from Drug A, both members of the same Drug-Class X

Modulate Include/Exclude File for labeled use Individuals in Administration of Fuller

of Drug B

Drug B Studies Fig. 2 US 2008/0280955 A1 Nov. 13, 2008

METHODS AND COMPOSITIONS FOR Genomic Polymorphisms’. U.S. Provisional Patent Applica SCREENING AND TREATMENT OF tion No. 60/648,957, filed Jan. 31, 2005, entitled “Composi DSORDERS OF BLOOD GLUCOSE tions and Methods For Treating, Preventing, and Diagnosing REGULATION Alzheimer's Disease.” U.S. application Ser. No. 10/956.224, filed Sep. 30, 2004, entitled “Methods for genetic analysis.” CROSS-REFERENCES TO RELATED U.S. Provisional Patent Application No. 60/653,672, filed APPLICATIONS Feb. 16, 2005, entitled “Parkinson's Disease-Related Disease Compositions and Methods.” U.S. application Ser. No. 0001. The present application is a nonprovisional of and 10/768,788, filed Jan. 30, 2004, entitled “Apparatus and claims the benefit of U.S. Provisional Application No. Methods for Analyzing and Characterizing Nucleic Acid 60/722.357 and U.S. Provisional Application No. 60/722, Sequences.” U.S. application Ser. No. 10/351,973, filed Jan. 636, both filed Sep. 30, 2005, and both of which are incorpo 27, 2003, entitled “Apparatus and Methods for Determining rated herein by reference in their entireties for all purposes. Individual Genotypes.” U.S. application Ser. No. 10/970,761, filed Nov. 20, 2004, entitled “Improved Analysis Methods BACKGROUND OF THE INVENTION and Apparatus for Individual Genotyping. U.S. application 0002 Recent advances in genetic analysis, e.g., genotyp Ser. No. 10/786,475, filed Feb. 24, 2004, entitled “Analysis ing, indicate that variations in both the natural history of Methods for Individual Genotyping,” and U.S. Provisional various diseases, as well as responses to treatments, including Patent Applications Nos. 60/643,006, 60/635,281 filed Jan. drug treatment, are linked to genetic variations among indi 11, 2005, and Dec. 9, 2004, respectively, both entitled “Mark viduals. As an example, disorders of blood glucose regula ers for Metabolic Syndrome Obesity and Insulin Resistance.” tion, including insulin resistance disorders, are a serious and the disclosures all of which are specifically incorporated growing health concern worldwide. These disorders, which herein by reference. The present invention builds upon this include Type I and Type II diabetes, Syndrome X, and obesity previous work. are treatable by a variety of lifestyle changes, as well as by drugs. Of the latter, one of the most effective categories is the SUMMARY OF THE INVENTION peroxisome proliferator-activated receptor (PPAR) modula 0004. The present application discloses methods for tors, especially PPAR-gamma agonists or partial agonists. screening an individual Suffering from a disorder of blood However, an obstacle to the optimal use of drugs to treat glucose regulation, e.g., an insulin resistance disorder, that disorders of blood glucose regulations is the incidence of include screening the individual for a genetic variation indi adverse effects, which are in Some cases serious enough to cating a predisposition to a response to an insulin sensitizer. cause use of the drug to be discontinued. For example, trogli In some embodiments, the individual is also screened for a taZone, which was marketed in the U.S. starting in April, 1997 phenotype indicating a predisposition to a response to an for the treatment of Type II diabetes, was voluntarily with insulin sensitizer. In some embodiments the invention further drawn in March 2000 due to incidents of idiosyncratic liver includes converting the results of said Screening into data that damage. Although these incidents occurred with a frequency is capable of transmission, and, in Some cases, transmitting of only about 1 in 100,000 patients, their severity was such said data to a location different from the location at which the that the drug was withdrawn. More common adverse effects data was created. The methods can also further include Such as edema, weight gain, and adverse effects on lipid administering or not administering an insulin sensitizer to the profiles, while not as severeas idiosyncratic liver damage, can individual based on the results of the screening of the indi nonetheless limit the therapeutic potential of insulin resis vidual; in some cases, administering or not administering the tance modulators. insulin sensitizer is done as part of a drug trial of the insulin 0003 Generally, distinct subgroups of patients respond to sensitizer. The insulin sensitizer for which the individual is a given drug with a given adverse effect. Experience with screened may be the same as or different from the insulin adverse effect profiles for other drugs indicates that the phe sensitizer that is administered or not administered to the indi notype of proclivity for a given adverse effect is a reflection of vidual. If the method includes administering an insulin sen genotype. Great progress has been made in relating genotype sitizer, they may also further include modulating the admin to phenotype in regards to disease etiology and response to istration of the insulin sensitizer based on the results of the treatment. See, e.g., U.S. patent application Ser. No. 11/043, screening of the individual. Modulation of administration can 689, filed Jan. 24, 2005, entitled “Associations Using Geno include, e.g., administering another therapeutic agent in addi types and Phenotypes: U.S. Provisional Application Ser. No. tion to the insulin sensitizer, or adjusting the dosage of the 60/280,530, filed Mar. 30, 2001, entitled “Identifying Human insulin sensitizer, route of administration of the insulin sen SNP Haplotypes, Informative SNPs and Uses Thereof: U.S. sitizer, frequency of administration of the insulin sensitizer, Provisional Application Ser. No. 60/313,264 filed Aug. 17. type of carrier of the insulin sensitizer, duration of treatment 2001, entitled “Identifying Human SNP Haplotypes, Infor with the insulin sensitizer, enantiomeric form of the insulin mative SNPs and Uses Thereof: U.S. Provisional Applica sensitizer, crystal form of the insulin sensitizer, or a combi tion Ser. No. 60/327,006, filed Oct. 5, 2001, entitled “Identi nation thereof, compared to if the screening had not been fying Human SNP Haplotypes, Informative SNPs and Uses performed. If the method includes not administering an insu Thereof: U.S. Provisional Application Ser. No. 60/332.550, lin sensitizer, it may further include administering treatment filed Nov. 26, 2002, entitled “Methods for Genomic Analy for the disorder of blood glucose regulation based on the sis”; U.S. application Ser. No. 10/106,097, filed Mar. 26, results of the screening of the individual. In certain embodi 2002, entitled “Methods for Genomic Analysis”; U.S. Pat. ments, the disorder of blood glucose regulation is diabetes No. 6,897,025, issued May 24, 2005, entitled “Genetic (e.g., Type II diabetes), obesity, or Syndrome X. The genetic Analysis Systems and Methods”; and U.S. application Ser. variation can be a single nucleotide polymorphism (SNP). In No. 10/284.444, filed Oct. 31, 2002, entitled “Human Some embodiments, the response to the insulin sensitizer is a US 2008/0280955 A1 Nov. 13, 2008

therapeutic response, and in Some embodiments, the response insulin sensitizer response nucleic acid. In some embodi to the insulin sensitizer is an adverse effect, Such as peripheral ments, these methods further include administering or not edema, dependent edema, generalized edema, pitting edema, administering an effective amount of an insulin sensitizer to weight increase, anemia, hypoglycemia, headache, increase said patient, based on the presence or absence of the hybrid in micturation frequency, diarrhea, increased appetite, tran ization complex, where the insulin sensitizer that is adminis sient ischemic attack, elevated liver enzymes, and combina tered or not administered may be the same as or different from tions thereof. the insulin sensitizer for which the individual was screened. 0005. In some embodiments, the insulin sensitizer for 0008. The invention still further provides an isolated which the individual is screened and/or that is administered or polypeptide partially or fully encoded by a nucleic acid that not administered to the individual is a thiazolidinedione specifically hybridizes to a region of a genomic sequence PPAR modulator, Such as rosiglitaZone, pioglitaZone, trogli upstream and downstream of an insulin sensitizer response taZone, netoglitazone and 5-BTZD. In some embodiments, nucleic acid, for use in screening, diagnostics, prognostics, the insulin sensitizer for which the individual is screened is a prevention, treatment, or study of response to an insulin sen thiazolidinedione PPAR modulator, such as rosiglitazone, sitizer. In some embodiments, the region extends from 10 kb pioglitaZone, troglitaZone, netoglitaZone and 5-BTZD, and upstream to 10 kb downstream of an insulin sensitizer the insulin sensitizer that is administered or not administered response nucleic acid, or from 5 kb upstream to 5 kb down to the individual is netoglitaZone. In some embodiments, the stream of an insulin sensitizer response nucleic acid, or from insulin sensitizer for which the individual is screened and the 1 kb upstream to 1 kb downstream of an insulin sensitizer insulin sensitizer that is administered or not administered to response nucleic acid. The invention also provides an anti the individual is netoglitazone. If an insulin sensitizer of the body, or an antigen-binding fragment thereof, which selec methods is netoglitaZone, in certain embodiments the netogli tively binds to a polypeptide as described for use in diagnos taZone is in an E crystal form. In some embodiments of the tics, prognostics, prevention, treatment, or study of response methods of the invention, the disorder of blood glucose regu to an insulin sensitizer. lation is Type II diabetes, the genetic variation is a SNP, the 0009. Also provided by the invention are kits for use in insulin sensitizer that is both screened and administered or diagnostics, prognostics, prevention, treatment, or study of not administered is netoglitaZone, and the response is a thera response to an insulin sensitizer that include a nucleic acid peutic response. In some embodiments, the disorder of blood that specifically hybridizes to a region of a genomic sequence glucose regulation is Type II diabetes, the genetic variation is upstream and downstream of an insulin sensitizer response a SNP, the insulin sensitizer that is screened and administered nucleic acidoran antibody an antibody, oran antigen-binding or not administered is netoglitaZone, and the response is an fragment thereof, which selectively binds to a polypeptide adverse effect. In some embodiments of the methods, the partially or fully encoded by a nucleic acid that specifically screening includes genotyping at least about 1, 10, 100, 1000, hybridizes to a region of a genomic sequence extending 10,000, 100,00, 500,000, 1,000,000, 2,000,000, or substan upstream and downstream of an insulin sensitizer response tially all of the genetic variations of the individual. nucleic acid. In some embodiments, the region extends from 0006. The invention also provides an isolated nucleic acid 10 kb upstream to 10 kb downstream of an insulin sensitizer that specifically hybridizes to a region of a genomic sequence response nucleic acid, or from 5 kb upstream to 5 kb down extending downstream and upstream of an insulin sensitizer stream of an insulin sensitizer response nucleic acid, or from response nucleic acid, for use in diagnostics, prognostics, 1 kb upstream to 1 kb downstream of an insulin sensitizer prevention, treatment, or study of an disorder of blood glu response nucleic acid. cose regulation. In some embodiments, the region extends 0010. The invention yet further provides a method for from 10 kb upstream to 10 kb downstream of an insulin predicting a response to an insulin sensitizer comprising com sensitizer response nucleic acid, or from 5 kb upstream to 5 kb paring a level of expression or activity of a polypeptide par downstream of an insulin sensitizer response nucleic acid, or tially or fully encoded by a nucleic acid that specifically from 1 kb upstream to 1 kb downstream of an insulin sensi hybridizes to a region of a genomic sequence extending tizer response nucleic acid. The insulin sensitizer can be a upstream and downstream of an insulin sensitizer response PPAR modulator, e.g., a thiazolidinedione PPAR modulator, nucleic acid. In some embodiments, the region extends from Such as netoglitaZone, rosiglitaZone, pioglitaZone, troglita 10 kb upstream to 10 kb downstream of an insulin sensitizer Zone, isaglitazone, 5-BTZD, and R119702. The disorder of response nucleic acid, or from 5 kb upstream to 5 kb down blood glucose regulation may be Type II diabetes. stream of an insulin sensitizer response nucleic acid, or from 1 kb upstream to 1 kb downstream of an insulin sensitizer 0007. The invention further provides methods for predict response nucleic acid. ing a presence or absence of a predisposition toward response 0011. The invention yet further provides business methods to an insulin sensitizer in an individual by contacting a sample that include using one or more genetic variations of the obtained from the individual with a nucleic acid that specifi human genome in association studies with Susceptibility to cally hybridizes to a region of genomic sequence extending response to an insulin sensitizer, and using associations found upstream and downstream of an insulin sensitizer response in the association study step to collaboratively or indepen nucleic acid; and detecting the presence or absence of a hybridization complex, where the presence or absence of a dently market products related to the insulin sensitizer. hybridization complex is predictive of the presence or absence of said predisposition toward response to said insulin INCORPORATION BY REFERENCE sensitizer in said individual. In some embodiments, the region 0012 All publications and patent applications mentioned extends from 10 kb upstream to 10 kb downstream of an in this specification are herein incorporated by reference in insulin sensitizer response nucleic acid, or from 5 kb their entireties to the same extent as if each individual publi upstream to 5 kb downstream of an insulin sensitizer response cation or patent application was specifically and individually nucleic acid, or from 1 kb upstream to 1 kb downstream of an indicated to be incorporated by reference. For example, pub US 2008/0280955 A1 Nov. 13, 2008

lications and patent applications of particular relevance to the differentiate between a subset of a plurality of individuals present invention include: U.S. application Ser. No. 10/956, who experience a particular response when administered a 224, filed Sep. 30, 2004, entitled “Methods for Genetic drug, e.g., an insulin sensitizer, and a Subset of the plurality of Analysis” and U.S. application Ser. No. 11/043.689, filed Jan. individuals who do not experience the particular response 24, 2005, entitled “Associations. Using Genotypes and Phe when administered the drug, e.g., insulin sensitizer. In some notypes.” embodiments the methods further include identifying one or more phenotypes that at least partly differentiate between the BRIEF DESCRIPTION OF THE DRAWINGS Subset who experience a particular response when adminis 0013 Certain novel features of the invention are set forth tered a drug, e.g., insulin sensitizer, and the Subset who do not with particularity in the appended claims. A better under experience the particular response when administered the standing of the features and advantages of the present inven drug, e.g., insulin sensitizer. The methods may further include tion will be obtained by reference to the following detailed predicting, based upon said one or more of the genetic varia description that sets forth illustrative embodiments, in which tions and/or phenotypes identified, whether a given indi the principles of the invention are utilized, and the accompa vidual is or is not predisposed to a particular response to a nying drawings: drug, e.g., an insulin sensitizer, where the drug for which the 0014 FIG. 1 is a high-level block diagram of a system that prediction is made may be the same as or may be different can be used for data entry, processing, display, storage, and from the drug for which one or more genetic variations were transfer in the methods and compositions of the invention. identified. In embodiments in which the drugs are different, 0015 FIG. 2 is a flow chart showing steps in the use of an the methods include predicting, based upon said one or more association study for one drug to modulate the clinical trial for of the genetic variations and/or phenotypes identified for the a second drug. first drug, e.g., insulin sensitizer, whethera given individual is or is not predisposed to a particular response to a second drug DETAILED DESCRIPTION OF THE INVENTION in the same class of drugs, e.g., in the class of insulin sensi tizers. I. Introduction 0019. In some embodiments, if the individual is adminis 0016. The invention provides methods, compositions, and tered a drug, e.g., an insulin sensitizer, on the basis of screen kits. Methods of the invention include methods of screening ing for one or more genetic variations indicating a response to and treatment of an individual including screening an indi a drug, the methods further include modulating the adminis vidual for one or more genetic variations indicating a predis tration of the drug, e.g., insulin sensitizer, based on the results position to a response to first drug and administering or not of the screening. As in other embodiments, the drug for which administering a second drug to the individual based on the the modulation is performed may be the same as or different results of the screening. In some embodiments the individual from the drug for which genetic variations indicate a suffers from a disorder. In some embodiments the first drug response. Modulating administration may include but is not and the second drug are the same; in other embodiments they limited to adjusting the dosage of the drug, e.g., insulin sen are different, e.g., different members of a class of drugs. Such sitizer, frequency of administration of the drug, duration of screening can be used, for example, to identify individuals treatment with the drug, form of the drug, or a combination who may benefit (or not benefit) from treatment with a drug, thereof. In some embodiments, if the individual is not admin individuals who may be enrolled (or excluded) from a clinical istered the drug, e.g., insulin sensitizer, the methods further trial, and/or individuals who may suffer (or not suffer) an include administering another treatment for the disorder, e.g., adverse reaction from a drug. In some embodiments one or for the disorder of blood glucose regulation. In some embodi more phenotypes may also be included in the screening step. ments, the methods include methods of Screening and treat Compositions and kits for use in the methods are also pro ment of an individual suffering from an disorder of blood vided by the invention. glucose regulation by Screening the individual for a genetic 0017. In some embodiments, methods of the invention variation indicating a predisposition to a particular response include methods of screening and treatment of an individual to a first insulin sensitizer; and administering, modulating the Suffering from a disorder of blood glucose regulation, e.g., an administration, or not administering a second insulin sensi insulin resistance disorder, that include Screening an indi tizer to the individual based on the results of the screening. In vidual in need of treatment for a disorder of blood glucose Some of these embodiments the second insulin sensitizer is regulation, e.g., an insulin resistance disorder, for a genetic the Subject of research, e.g., a clinical trial. variation indicating a predisposition to a response to an insu 0020. In one aspect, compositions of the invention include lin sensitizer, and administering or not administering an insu an isolated nucleic acid that specifically hybridizes to a region lin sensitizer to the individual based on the results of the of a genomic sequence extending upstream and downstream screening. The insulin sensitizer for which the individual is of a nucleic acid associated with a response to a drug, e.g., an screened may be the same as or different from the insulin insulin sensitizer response nucleic acid, for use in diagnos sensitizer that is administered or not administered to the indi tics, prognostics, prevention, treatment, or study of a disorder, vidual. Such screening can be used, for example, to identify e.g., a disorder of blood glucose regulation. In one aspect, individuals who may benefit (or not benefit) from treatment compositions of the invention include an isolated nucleic acid with an insulin sensitizer, individuals who may be enrolled that specifically hybridizes to a region of a genomic sequence (or excluded) from a clinical trial, and/or individuals who that is in linkage disequilibrium with a nucleic acid associated may suffer (or not suffer) an adverse reaction to an insulin with a response to a drug, e.g., an insulin sensitizer response sensitizer. In some embodiments one or more phenotypes nucleic acid, for use in diagnostics, prognostics, prevention, may also be included in the screening step. treatment, or study of a disorder, e.g., a disorder of blood 0018. In one aspect, the methods of the invention include glucose regulation. Treatment of the disorder can include identifying one or more genetic variations that at least partly treatment with another drug in the same class of drugs as the US 2008/0280955 A1 Nov. 13, 2008

drug for which a response is associated with the nucleic acid. of the invention under conditions appropriate forbinding; and In some embodiments, the region extends from 10 kb assessing the sample for the presence or amount of binding of upstream to 10 kb downstream of the nucleic acid, or from 5 the antibody to the polypeptide. The invention yet further kb upstream to 5 kb downstream of the nucleic acid, or from provides methods for predicting a response to a drug, e.g., an 1 kb upstream to 1 kb downstream of the nucleic acid. insulin sensitizer by comparing the level of expression or 0021. In another aspect, compositions of the invention activity of a polypeptide of the invention in a test sample from include an isolated polypeptide encoded at least in part by an a patient with the level of expression or activity of the same isolated nucleic acid that specifically hybridizes to a region of polypeptide in a control sample, where a difference in the a genomic sequence extending downstream and upstream of level of expression or activity between the test sample and a nucleic acid associated with a response to a drug, e.g., an control sample is predictive of a response to a drug, e.g., an insulin sensitizer response nucleic acid for use in diagnostics, insulin sensitizer. prognostics, prevention, treatment, or study of a disorder, 0025. The invention also provides business methods that e.g., a disorder of blood glucose regulation. Treatment of the include using the genetic variations found in the human disorder can include treatment with another drug in the same genome in association studies with responsiveness to an insu class of drugs as the drug for which a response is associated lin sensitizer, using associations from the association step in with the nucleic acid. In some embodiments, the region a discovery process; and collaboratively or independently, extends from 10 kb upstream to 10 kb downstream of the marketing products from the discovery process. The inven nucleic acid, or from 5 kb upstream to 5 kb downstream of the tion further provides business methods that include using the nucleic acid, or from 1 kb upstream to 1kb downstream of the genetic variations found in the human genome in association nucleic acid. studies with responsiveness to a first drug in a class of drugs; 0022. In yet another aspect, the invention provides an anti using associations from the association step in a discovery body or an antigen-binding fragment thereof, which selec process involving at least a second drug in the class of drugs; tively binds to an isolated polypeptide encoded at least in part and collaboratively or independently, marketing products by an isolated nucleic acid that specifically hybridizes to a from the discovery process. region of a genomic sequence extending downstream and upstream of a nucleic acid associated with a response to a II. Disorders of Blood Glucose Regulation drug, e.g., an insulin sensitizer response nucleic acid for use 0026. The invention relates to methods and compositions in diagnostics, prognostics, prevention, treatment, or study of for the diagnosis, prognosis, prevention, treatment, or study a disorder, e.g., a disorder of blood glucose regulation. Treat of disorder of blood glucose regulation, including insulin ment of the disorder can include treatment with another drug resistance disorders. in the same class of drugs as the drug for which a response is 0027 “Disorders of blood glucose regulation, as used associated with the nucleic acid. In some embodiments, the herein, encompasses disorders that are associated with an region extends from 10 kb upstream to 10 kb downstream of inability to regulate blood glucose within optimal limits (of the nucleic acid, or from 5 kb upstream to 5 kb downstream of ten, though not always, due to an insulin resistance disorder) the nucleic acid, or from 1kb upstream to 1 kb downstream of as well as related phenotypes (e.g. complications that result the nucleic acid. from insulin resistance). Disorders of blood glucose regula 0023 The invention further provides kits that include one tion include, but are not limited to, diabetes (both Type I and or more of the nucleic acids, polypeptides, and/or antibodies Type II), Syndrome X, and associated symptoms or compli of the invention. cations including Such conditions as impaired glucose toler 0024. In addition the invention provides methods for ance (IGT), impaired fasting glucose (IFG), obesity, nephr assaying the presence of a nucleic acid, e.g., an insulin sen opathy, neuropathy, retinopathy, atherosclerosis, polycystic sitizer response nucleic acid in a sample for use in diagnos ovary syndrome, hypertension, ischemia, stroke, heart dis tics, prognostics, prevention, treatment, or study of a disorder, ease, irritable bowel disorder, inflammation, and cataracts. e.g., a disorder of blood glucose regulation, by contacting the Examples of a prediabetic state include IGT and IFG. sample with a nucleic acid of the invention under stringent 0028. Insulin, which is produced by the pancreas in hybridization conditions; and detecting a presence of a response to changes in blood glucose levels, regulates tissue hybridization complex. In some embodiments, methods uptake of glucose. As used herein, “insulin resistance disor include assaying the expression level of an RNA encoded by ders' includes disorders in which there is a physiological a nucleic acid, e.g., an insulin sensitizer response nucleic acid state wherein normal tissue responsiveness to insulin is in a sample for use in diagnostics, prognostics, prevention, impaired. In most cases, to compensate for insulin resistance, treatment, or study of a disorder, e.g., a disorder of blood the pancreas will produce more insulin. As used herein, “insu glucose regulation, by contacting the sample with a nucleic lin resistance disorders' are considered a subgroup of disor acid of the invention under Stringent hybridization condi ders of blood glucose regulation, whether or not they yet tions; and detecting a presence of a hybridization complex. In manifest as inability to regulate blood glucose within optimal Some embodiments, methods include predicting a presence or limits. absence of a predisposition toward response to a drug, e.g., an 0029 Diabetes is a major category of disorders of blood insulin sensitizer in an individual by detecting the presence or glucose regulation. It is a chronic disorder affecting carbohy absence of the hybridization complex. The drug may be the drate, fat and protein metabolism in animals. Type I diabetes same as or different from the drug for which the nucleic acid mellitus, which comprises approximately 10% of all diabetes is associated to a response. The invention further provides cases, was previously referred to as insulin-dependent diabe methods for assaying the presence or amount of a polypeptide tes mellitus (“IDDM) or juvenile-onset diabetes. This dis of the invention for use in diagnostics, prognostics, preven ease is characterized by a progressive loss of insulin secretory tion, treatment, or study of a disorder, e.g., a disorder of blood function by beta cells of the pancreas. This characteristic is glucose regulation, by contacting a sample with an antibody also shared by non-idiopathic, or “secondary”, diabetes hav US 2008/0280955 A1 Nov. 13, 2008 ing its origins in pancreatic disease. Type I diabetes mellitus sitizers, e.g., adverse response, and/or administering or not is associated with the following clinical signs or symptoms: administering drugs, e.g., insulin sensitizers to the individual persistently elevated plasma glucose concentration or hyper based on Such screening. This section describes certain drugs glycemia; polyuria; polydipsia and/or hyperphagia; chronic ofuse in embodiments of the invention. Further useful drugs microvascular complications such as retinopathy, nephropa for the invention are described in section IVC, Association thy and neuropathy; and macrovascular complications such studies and methods for classes of drugs. as hyperlipidemia and hypertension which can lead to blind ness, end-stage renal disease, limb amputation and myocar A. A. Insulin Sensitizers dial infarction. 0030 Type II diabetes mellitus (non-insulin-dependent 0036. One class of drugs included in certain embodiments diabetes mellitus or NIDDM) is a metabolic disorder involv of the invention is an insulin sensitizer. The term “insulin ing the dysregulation of glucose metabolism and impaired sensitizer, or “insulin sensitizing agent, as used herein, insulin sensitivity. Type II diabetes mellitus usually develops refers to any agent capable of enhancing either secretion ofor, in adulthood and is associated with the body's inability to more typically, tissue sensitivity to, insulin. Non-exclusive utilize or make sufficient insulin. In addition to the insulin examples of insulin sensitizers include metformin, Sulfony resistance observed in the target tissues, patients suffering lureas, alpha glucosidase inhibitors and PPAR modulators, from Type II diabetes mellitus have a relative insulin defi including thiazolidinediones. Further examples of insulin ciency—that is, patients have lower than predicted insulin sensitizers are described below. levels for a given plasma glucose concentration. Type II dia 0037. The thiazolidinediones are examples of PPAR betes mellitus is characterized by the following clinical signs modulators, which are one class of insulin sensitizers for use or symptoms: persistently elevated plasma glucose concen in the present invention. The term “PPAR modulator, as used tration or hyperglycemia; polyuria; polydipsia and/or hyper herein, refers to peroxisome proliferator-activated receptor phagia; chronic microvascular complications such as retin agonists, partial agonists, and antagonists. The modulator opathy, nephropathy and neuropathy; and macrovascular may, selectively or preferentially, affect PPAR alpha, PPAR complications such as hyperlipidemia and hypertension gamma, or both receptors. Typically, the modulator increases which can lead to blindness, end-stage renal disease, limb insulin sensitivity. According to one aspect, the modulator is amputation and myocardial infarction. a PPARgamma agonist. One PPARgamma agonist used in 0031. Syndrome X, also termed Insulin Resistance Syn embodiments of the invention is 5-(6-(2-fluorobenzyl)oxy drome (IRS), Metabolic Syndrome, or Metabolic Syndrome 2-naphthylmethyl-2,4-thiazolidinedione; (MCC-555 or X, presents symptoms or risk factors for the development of “netoglitazone'). Type II diabetes mellitus and cardiovascular disease, includ ing impaired glucose tolerance (IGT), impaired fasting glu B. B. Insulin Sensitizers PPAR Modulators cose (IFG), hyperinsulinemia, insulin resistance, dyslipi 0038. One class of insulin sensitizers of the invention is demia (e.g., high triglycerides, low HDL), hypertension and PPAR modulators, and in particular PPAR-gamma modula obesity. tors, e.g., PPAR-gamma agonists. PPAR modulators include 0032. Therapy for Type I diabetes patients has consistently the PPAR-alpha, PPAR-delta (also called PPAR-beta), and focused on administration of exogenous insulin, which may PPAR-gamma agonists. Especially useful are the thiazo be derived from various sources (e.g., human, bovine, porcine lidinediones (TZDs), which were developed in the 70's and insulin). The use of heterologous species material gives rise to 80's by screening newly synthesized compounds for their formation of anti-insulin antibodies which have activity-lim ability to lower blood glucose in diabetic rodents. Three mol iting effects and result in progressive requirements for larger ecules from this class, troglitaZone, rosiglitaZone, and piogli doses in order to achieve desired hypoglycemic effects. taZone, were ultimately approved for the treatment of patients 0033 Typical treatment of Type II diabetes mellitus with Type II diabetes. Although these compounds were devel focuses on maintaining the blood glucose level as near to oped without an understanding of their molecular mechanism normal as possible with lifestyle modification relating to diet of action, by the early 90’s evidence began to accumulate and exercise, and when necessary, the treatment with antidia linking the thiazolidinediones to the nuclear receptor PPAR betic agents, insulin or a combination thereof. gamma. It was ultimately demonstrated that these molecules 0034. Although insulin resistance is not always treated in were high affinity ligands of PPAR-gamma and that they all Syndrome X patients, those who exhibit a prediabetic state increased transcriptional activity of the receptor. Without (e.g., IGT. IFG), where fasting glucose levels may be higher wishing to be bound by theory, multiple lines of evidence now than normal but are not at the diabetes diagnostic criterion, are indicate that the antidiabetic activities of the thiazolidinedi treated in Some countries (e.g., Germany) with metforminto ones are mediated by their direct interaction with the receptor prevent diabetes. The anti-diabetic agents may be combined and the Subsequent modulation of PPAR-gamma target gene with pharmacological agents for the treatment of the con expression. comitant co-morbidities (e.g., antihypertensives for hyper 0039. Thiazolidinediones of use in the methods of the tension, hypolipidemic agents for lipidemia). invention include: (1) rosiglitaZone; (2) pioglitaZone; (3) tro glitazone; (4) netoglitazone (also known as MCC-555 or III. Drugs of Use in the Invention isaglitazone or neoglitazone); and (5) 5-BTZD. 0035. The methods and compositions of the invention 0040. Accordingly, in some embodiments, the invention include the study and use of drugs, e.g., insulin sensitizers, provides a method of Screening of an individual Suffering and include performing association studies for determining from a disorder of blood glucose regulation that includes genotypic and/or phenotypic traits associated with respon screening the individual for a genetic variation indicating a siveness to drugs, e.g., insulin sensitizers, screening individu predisposition to a response to an insulin sensitizer, where the als for predisposition to response to drugs, e.g., insulin sen insulin sensitizer for which the individual is screened is a US 2008/0280955 A1 Nov. 13, 2008

thiazolidinedione PPAR modulator such as rosiglitazone, (AZ-242): (20) GW 9820 (fibrate); (21) GW 1929 (N-(2- pioglitaZone, troglitaZone, netoglitaZone, or 5-BTZD; in benzoylphenyl)-O-(2-(methyl-2-pyridinylamino)ethyl)-L- Some embodiments, the invention provides a method of tyrosine, known as GW 2331, PPAR agonist); (22) SB screening of an individual suffering from a disorder of blood 219994 ((S)-4-(2-(2-benzoxazolylmethylamino)ethoxy)-al glucose regulation that includes screening the individual for a pha-(2.2.2-trifluoroethoxy)benzen epropanoic acid or 3-(4- genetic variation indicating a predisposition to a response to (2-(N-(2-benzoxazolyl)-N-methylamino)ethoxy)phenyl)-2 an insulin sensitizer, the insulin sensitizer that is administered (S)-(2.2.2-trifluoroethoxy)propionic acid or benzenepro or not administered to the individual is selected from the panoic acid, 4-(2-(2-benzoxazolylmethylamino)ethoxy)-al group consisting of rosiglitaZone, pioglitaZone, troglitaZone, pha-(2.2.2-trifluoroethox-Y)-, (alphaS)-, PPAR alpha/gamma netoglitazone, or 5-BTZD. Non-thiazolidinedione PPAR agonist); (23) L-796449 (PPAR alpha/gamma agonist); (24) modulators that may also be included in certain methods of Fenofibrate (propanoic acid, 2-4-(4-chlorobenzoyl)phe the invention include muraglitazar and fargilitazar, described noxy-2-methyl-, 1-methylethyl ester, known as TRICOR, below. LIPCOR, LIPANTIL, LIPIDIL MICRO PPAR alpha ago 0041. Other PPAR modulators of use in the invention nist); (25) GW-9578 (PPAR alpha agonist); (26) GW-2433 include modulators that have recently been the subject of (PPAR alpha/gamma agonist); (27) GW-0207 (PPARgamma clinical trials: (1) Muraglitazar (PPARgamma and alpha ago agonist); (28) LG-100641 (PPARgamma agonist); (29) nist, Bristol-Myers/Merck); (2) Galida tesaglitazar (PPAR LY-300512 (PPARgamma agonist); (30) NID525-209 (NID gamma and alpha agonist, AstraZeneca); (3) 677954 (PPAR 525); (31)VDO-52 (VDO-52); (32) LG 100754 (peroxisome gamma, alpha, and delta agonist, GlaxoSmithKline); (4) proliferator-activated receptoragonist); (33) LY-510929 (per MBX-102 (PPARgamma partial agonist/antagonist, Metab oxisome proliferator-activated receptor agonist); (34) bex olex); (5) T131 (PPARgamma selective modulator, Tularik/ arotene (4-(1-(3.5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2- Amgen); (6) LY818 (PPARgamma and alpha partial agonist, naphthalenyl)ethenyl)benzoic acid, known as TARGRETIN, Eli Lilly/Ligand); (7) LY929 (PPARgamma and alpha ago TARGRETYN, TARGREXIN; also known as LGD 1069, LG nist, Eli Lilly/Ligand); and (8) PLX204 (PPARgamma, 100069, LG 1069, LDG 1069, LG 69, RO 264455); and (35) alpha, and delta agonist, Plexxikon). See, e.g., BioCentury, GW-1536 (PPAR alpha/gamma agonist). Jun. 14, 2004. Further PPAR modulators include LY 519818, 0044. Other thiazolidinedione and non-thiazolidinedione L-783483, L-165461, and L-165041. insulin sensitizers of use in the invention are described in, 0042 Additionally, the non-thiazolidinediones that act as e.g., Leff and Reed (2002) Curr. Med. Chem.—Imun., insulin-sensitizing agents include, but are not limited to: (1) Endoc.,& Metab. Agents 2:33-47: Reginato et al. (1998).J. JT-501 (JTT 501, PNU-1827, PNU-716-MET-0096, or PNU Biol. Chem., 278 32679-32654; Way et al. (2001) J. Biol. 182716: 4-(4-(2-(5-methyl-2-phenyl-oxazol-4-yl)ethoxy) Chem. 276 25651-25653; Shiraki et al. (2005).JBC Papers in benzyl)isoxazolidine-3,5-dione; (2) KRP-297 (5-(2,4-di Press, published on Feb. 4, 2005, as Manuscript oxothiazolidin-5-ylmethyl)-2-methoxy-N-(4-(tri-fluorom M500901200, and U.S. Pat. Nos. 4,703,052: 6,008,237; ethyl)benzyl)benzamide or 5-(2,4-dioxo-5-thiazolidinyl) 5,594,016; 6,838,442; 6,329,423: 5,965,589; 6,677,363; methyl)-2-methoxy-N-(4-(trifluoromethyl)phenyl)methyl) 4,572,912; 4,287,200; 4,340,605; 4,438,141; 4,444,779; benzamide); and (3) Farglitazar (L-tyrosine, N-(2- 4,572,912; 4,687,777; 4,725,610; 5,232,925; 5,002,953; benzoylphenyl)-O-(2-(5-methyl-2-phenyl-4-oxazolyl)ethyl) 5,194,443; 5,260,445; 6,300,363; 6,034,110; and 6,541,493; O N-(2-benzoylphenyl)-O-(2-(5-methyl-2-phenyl-4-ox U.S. Patent Application Publications 2002/0042441; 2004/ azolyl)ethyl)-L-tyrosine, or (S)-2-(2-benzoylphenylamino)- O198774 and 2003/0045553; EP Patent Nos. O139421 and 3-(4-12-(5-methyl-2-phenyl-2-oxazo-4-yl)ethoxyphenyl) 0332332; and PCT Publication Nos. WO95/35314; WO propionic acid, or GW2570 or GI-262570). 00/31055; WO 01/3640, all of which are incorporated by 0043. Other agents have also been shown to have PPAR reference herein in their entirety. modulator activity such as PPAR-gamma, SPPAR-gamma, C. Netoglitazone and/or PPAR-alpha/delta agonist activity. Examples are: (1) AD 5075 (5-(4-(2-hydroxy-2-(5-methyl-2-phenyloxazol-4- 0045 One thiazolidinedione PPAR modulator for use in yl)ethoxy)benzyl)-thiazolidine-2,4-dione); (2) R 119702 (or the methods of the invention is netoglitazone (5-(6-(2-fluo Cl1037 or CS 011); (3) CLX-0940 (peroxisome proliferator robenzyl)oxy-2-naphthylmethyl-2,4-thiazolidinedione; activated receptor alpha agonist/peroxisome proliferator-ac MCC-555). Structures and methods of preparation of netogli tivated receptor gamma agonist); (4) LR-90 (2.5.5-tris(4- taZone and various forms of netoglitaZone of use in the inven chlorophenyl)-1,3-dioxane-2-carboxylic acid, PPAR alpha/ tion are described in, e.g., U.S. Pat. Nos. 5,594,016; 6.541, gamma agonist); (5) CLX-0921 (PPARgamma agonist); (6) 493: 6,541,493; 6,838,442; U.S. Patent Application No. CGP-52608 (PPAR agonist); (7) GW-4098.90 (PPAR ago 2004/0198774 and 2003045553; PCT Publication Nos. WO nist); (8) GW-7845 (2C(S)-1-carboxy-2-(4-(2-(5-methyl-2- 00/31055; WO 01/36401; WO 03/018010, and WO phenyl-oxazol-4-yl)-ethoxy)-phenyl)-ethyamino)-benzoic 00/73252: Japanese Patent Unexamined Publication (KO acid methyl ester, PPAR agonist); (9) L-764406 (2-benzene KAI) Nos. (Hei) 6-247945/1994 and (Hei) 10-1397.68/1998: sulphonylmethyl-3-chloroquinoxaline, PPAR agonist); (10) Japanese Patents 2001 172179 and 2003040877; and Regi LG-101280 (PPAR agonist); (11) LM-4156 (PPAR agonist); nato et al. (1998).J. Biol. Chem. 273: 32679-32684; all of (12) Risarestat (CT-112, (+)-5-(3-ethoxy-4-(pentyloxy)phe which are incorporated by reference herein in their entirety. nyl-2,4-thiazolidinedione aldose reductase inhibitor); (13) 0046. It has been reported that netoglitazone is more effi YM 440 (PPAR agonist); (14) AR-HO49020 (PPAR agonist); cacious than pioglitaZone and troglitaZone in lowering (15) GW 0072 ((+)-(2S,5S)-4-(4-(5-((dibenzy carbomoyl) plasma glucose, insulin, and triglyceride levels and that it is methyl)-2-heptlyl-4-oxothiazolidin-3-ylbutyl)benzoic acid); about three-fold more potent than rosiglitazone. The activity (16) GW409544 (GW-544 or GW-409544); (17) NN 2344 of netoglitaZone appears to be context-specific, as in some (DRF 2593); (18) NN 622 (DRF 2725); (19) AR-H039242 cell types it behaves as a full agonist of PPAR-gamma and as US 2008/0280955 A1 Nov. 13, 2008 a partial agonist orantagonist in others. In addition, it appears polymorphic forms of netoglitaZone known in the art may be to modulate PPAR-alpha and delta as well. See, e.g., U.S. used in the methods of the invention, either separately or in Patent Application Publication No. 2004/0198774. combination. Thus, the methods of the invention include association studies using any or all of the polymorphic forms D. Forms of Drugs ofnetoglitaZone, as well as screening and treatment using any 0047. Some compounds useful in the invention, including or all of the polymorphic forms of netoglitaZone, composi the TZD PPAR modulators such as netoglitazone, may have tions and kits based on these forms, and the like. one or more asymmetric carbon atoms in their structure. It is 0051 Polymorphic forms of netoglitazone include the A, intended that the present invention include within its scope B, C, D, E and amorphous crystal forms described in PCT the stereochemically pure isomeric forms of the compounds Published Application No. WO 01/36401 and in U.S. Pat. No. as well as their racemates. Stereochemically pure isomeric 6,541,493; for example, the E form is described in PCT Pub forms may be obtained by the application of art known prin lished Application No. WO 01/36401. ciples. Diastereoisomers may be separated by physical sepa 0.052 Some of the compounds described herein may exist ration methods such as fractional crystallization and chro with different points of attachment of hydrogen coupled with matographic techniques, and enantiomers may be separated double bond shifts, referred to as tautomers. An example is a from each other by the selective crystallization of the diaste carbonyl (e.g. a ketone) and its enol form, often known as reomeric salts with optically active acids or bases or by chiral keto-enol tautomers. The individual tautomers as well as chromatography. Pure stereoisomers may also be prepared mixtures thereof are encompassed within the invention. synthetically from appropriatestereochemically pure starting 0053 Prodrugs are compounds that are converted to the materials, or by using stereospecific reactions. claimed compounds as they are being administered to a 0048. Some compounds useful in the invention may have patient or after they have been administered to a patient. The various individual isomers, such as trans and cis, and various prodrugs are compounds of this invention, and the active alpha and beta attachments (below and above the plane of the metabolites of the prodrugs are also compounds of the inven drawing). In addition, where the processes for the preparation tion. of the compounds according to the invention give rise to E. Responses to Drugs mixture of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. 0054 Responses to drugs, e.g., insulin sensitizers, that are The compounds may be prepared as a single stereoisomer or observed or predicted in the methods of the invention include in racemic form as a mixture of some possible stereoisomers. therapeutic responses and responses that are not therapeutic The non-racemic forms may be obtained by either synthesis (e.g., side effects. Such as adverse effects.). Included in or resolution. The compounds may, for example, be resolved “response' and “responsiveness” as those terms are used into their components enantiomers by standard techniques, herein is no response or no detectable response. Hence, in Such as the formation of diastereomeric pairs by Salt forma Some cases, a genetic variation or phenotype associated with tion. The compounds may also be resolved by covalent link a response to a drug, e.g., insulin sensitizer, is associated with age to a chiral auxiliary, followed by chromatographic sepa an effect (response) when that drug, e.g., insulin sensitizer is ration and/or crystallographic separation, and removal of the administered, whereas in other cases a genetic variation or chiral auxiliary. Alternatively, the compounds may be phenotype associated with a response to a drug, e.g., insulin resolved using chiral chromatography. Unless otherwise sensitizer is associated with a lack of a detectable effect noted, the scope of the present invention is intended to cover (response) when that drug, e.g., insulin sensitizer is adminis all Such isomers or Stereoisomers perse, as well as mixtures tered. of cis and trans isomers, mixtures of diastereomers and race 0055. Therapeutic responses include any response to a mic mixtures of enantiomers (optical isomers) as well. drug that results in an improvement or amelioration of the 0049. In addition, compounds of the invention may be condition for which the drug is administered and/or compli prepared in various polymorphic forms. For example, insulin cations due to the condition for which the drug is adminis sensitizers of use in the invention can occur in polymorphic tered. For example, if the drug is an insulin sensitizer, “thera forms, and any or all of the polymorphic forms of these peutic response' includes any response that results in an insulin sensitizers are contemplated for use in the invention. improvement or amelioration of sensitivity to insulin and/or Polymorphism in drugs may alter the stability, solubility and complications due to lack of insulin sensitivity. One thera dissolution rate of the drug and result in different therapeutic peutic response is increased sensitivity to insulin, which may efficacy of the different polymorphic forms of a given drug. be evidenced by a decrease in blood glucose levels, either The term polymorphism is intended to include different with or without the administration of exogenous insulin. physical forms, crystal forms, and crystalline/liquid crystal Therapeutic responses to a drug, e.g., insulin sensitizer, may line/non-crystalline (amorphous) forms. Polymorphism of be further classified by degree of response; any suitable gra compounds of therapeutic use has is significant, as evidenced dation of degree of response may be used, including relatively by the observations that many antibiotics, antibacterials, tran broad gradations (e.g., strong responder, moderate responder, quilizers etc., exhibit polymorphism and some? one of the and weak responder) and relatively more narrow gradations polymorphic forms of a given drug may exhibit Superior (e.g., ranking responses as a percentile of maximum observed bioavailability and consequently show much higher activity response and dividing responses into, e.g., deciles, quartiles, compared to other polymorphs. For example, Sertraline, and the like). Frentizole, Ranitidine, Sulfathiazole, and Indomethacine are 0056 Responses to a drug that are not therapeutic effects Some of the pharmaceuticals that exhibit polymorphism. can include adverse effects. For example, some PPAR modu 0050. Some embodiments of the invention include the use lators are known to exhibit non-therapeutic effects, including of netoglitaZone in one of its polymorphic forms. Netoglita adverse effects. Although certain PPAR modulators have Zone can be prepared in various polymorphic forms. Any been shown to be safe and effective in FDA testing, all show US 2008/0280955 A1 Nov. 13, 2008

varying degrees of adverse effects, some of which are serious ods of the invention involve the administration of one or more enough to halt clinical trials or to stop the use of the approved agents that are not the agent, e.g., insulin sensitizer for which drug. For example, troglitaZone, which was marketed in the the individual is screened. In some embodiments, the meth U.S. starting in April, 1997 for the treatment of Type II dia ods of the invention involve the administration of one or more betes, was voluntarily withdrawn in March 2000 due to inci agents that are not the insulin sensitizer for which the indi dents of idiosyncratic liver damage. Although these incidents vidual is screened in combination with the insulin sensitizer occurred with a frequency of only about 1 in 100,000 patients, for which the individual is screened. their severity was such that the drug was withdrawn. More 0061. In some embodiments in which the insulin sensitizer common adverse effects such as edema, weight gain, and for which the individual is screened is not administered, adverse effects on lipid profiles, while not as severe as idio another therapeutic agent can be administered to the indi syncratic liver damage, can nonetheless limit the therapeutic vidual in place of the insulin sensitizer for which the indi potential of insulin resistance modulators. vidual is screened. For example, an individual may be 0057. In association and diagnostic methods of the inven screened for responsiveness to netoglitaZone, and if the tion, “adverse effects.” of a drug, e.g., of a PPAR modulator, results of the screening indicate that the individual is predis include an adverse effect on the user of the drug. Exemplary posed to adverse effects of netoglitazone, another PPAR adverse effects of insulin sensitizers include peripheral modulator, Such as rosiglitaZone, pioglitaZone, or troglita edema, dependent edema, generalized edema, pitting edema, Zone, may be administered instead. Alternatively, another weight increase or decrease, anemia, hypoglycemia, head insulin sensitizer that is not a TZD PPAR modulator may be ache, increase in micturation frequency, diarrhea, increased administered to the individual based on the results of the or decreased appetite, transientischemic attack, elevated liver Screening. enzymes, and combinations thereof. Non-therapeutic effects, 0062 Other therapeutic agents include the insulin sensi e.g., adverse effects, may be measured by any means known tizers described above, or non-insulin sensitizing agents. See, in the art or apparent to the skilled artisan. As with therapeutic e.g., Leff and Reed (2002) Curr. Med. Chem.—Imun., responses, nontherapeutic responses, e.g., adverse effects, to Endoc.& Metab. Agents 2:33-47: Reginato et al. (1998) J. a drug, e.g., insulin sensitizer, may be further classified by Biol. Chem., 278 32679-32654; Way et al. (2001) J. Biol. degree of response and any suitable gradation of degree of Chem. 276 25651-25653; Shiraki et al. (2005).JBC Papers in response may be used. Press, published on Feb. 4, 2005, as Manuscript M500901200, and U.S. Pat. Nos. 4,703,052: 6,008,237; F. Additional Agents for Use in the Invention 5,594,016; and 6,541,493: U.S. Patent Application Publica 0058 Methods of the invention include screening an indi tion 2004/0198774 and 2003/0045553; and PCT Publication vidual for a genetic variation and/or phenotypic variation that Nos. WO 00/31055; WO 01/3640, all of which are incorpo indicates responsiveness to a drug, e.g., an insulin sensitizer rated by reference herein in their entirety. prior to determining whether or not to administer a drug, e.g., 0063. Other agents useful in the methods of the invention an insulin sensitizer to an individual. include, but are not limited to: 0059. Such screening can be used, for example, to identify 0064 1. Biguanides, which decrease liverglucose produc individuals who may benefit (or not benefit) from treatment tion and increases the uptake of glucose. Examples include with the drug, e.g., insulin sensitizer, individuals who may be metformin Such as: (1) 1,1-dimethylbiguanide (e.g., Met enrolled (or excluded) from a clinical trial, and/or individuals formin-DepoMed, Metformin-BioVail Corporation, or MET who may suffer (or not suffer) an adverse response to the FORMINGR (metformingastric retention polymer)); and (2) drug, e.g., insulin sensitizer. In some embodiments, the metformin hydrochloride (N,N-dimethylimidodicarbonim results of the screening determine whether drug, e.g., insulin idic diamide monohydrochloride, also known as LA 6023, sensitizer is administered or is not administered to aparticular BMS 207 150, GLUCOPHAGE, or GLUCOPHAGEXR. individual. In some embodiments in which the drug, e.g., 0065 2. Alpha-glucosidase inhibitors, which inhibit insulin sensitizer is administered, the administration of the alpha-glucosidase, and thereby delay the digestion of carbo drug is modulated based on the results of the screening of the hydrates. The undigested carbohydrates are Subsequently individual. Such modulation may involve adjustment of the broken down in the gut, reducing the post-prandial glucose administration of the drug. For example, modulating admin peak. Examples include, but are not limited to: (1) acarbose istration may include: adjusting the dosage of the drug, route (D-glucose, O-4,6-dideoxy-4-(((1S-(1alpha,4alpha,5beta, of administration of the drug, duration of treatment with the 6alpha))-4,5,6-trihydroxy-3-(hydroxymethyl)-2-cyc-lo drug, or frequency of administration of the drug; changing the hexen-1-yl)amino)-alpha-D-glucopyranosyl-(1-4)-O-alpha type of carrier of the drug, enantiomeric form of the drug, D-glucopyranosyl-(1-4)-, also known as AG-5421, Bay-g- crystal form of the drug, tautomeric form of the drug; admin 542, BAY-g-542, GLUCOBAY, PRECOSE, GLUCOR, istering a fragment, analog, and/or variant of the drug; or a PRANDASE, GLUMIDA, or ASCAROSE); (2) Miglitol combination thereof. (3,4,5-piperidinetriol, 1-(2-hydroxyethyl)-2-(hydroxym 0060 Modulation of the administration of the drug, e.g., ethyl)-, (2R(2alpha, 3beta, 4alpha, 5beta)- or (2R,3R.4R, insulin sensitizer can also include administration of one or 5S)-1-(2-hydroxyethyl)-2-(hydroxymethyl-3,4,5-piperidin more other therapeutic agents that are not the drug for which etriol, also known as BAY 1099, BAY M1099, BAY-m-1099, the individual is screened, in addition to administration of the BAYGLITOL, DIASTABOL, GLYSET, MIGLIBAY, drug for which the individual is screened. For non-insulin MITOLBAY, PLUMAROL); (3) CKD-711 (0-4-deoxy-4- sensitizers, another drug in the class of drugs may be admin ((2,3-epoxy-3-hydroxymethyl-4,5,6-trihydro-xycyclohex istered. Drug classes are described in detail below. In the case ane-1-yl)amino)-alpha-b-glucopyranosyl-(1-4)-alpha-D- of insulin sensitizers, the other therapeutic agent may be, e.g., glucopyran-osyl-(1-4)-D-glucopyranose); (4) emiglitate (4- another insulin sensitizer, or an agent that is not an insulin (2-((2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)-1- sensitizer, as described herein. Thus, in some cases, the meth piperidinyl)ethoxy)benzoic acid ethyl ester, also known as US 2008/0280955 A1 Nov. 13, 2008

BAY o 1248 or MKC 542); (5) MOR 14 (3,4,5-piperidin 0068 5. Insulin secretagogues, which increase insulin etriol, 2-(hydroxymethyl)-1-methyl-, (2R-(2alpha, 3beta, production by stimulating pancreatic beta cells, such as: (1) 4alpha, 5beta))-, also known as N-methyideoxynojirimycin asmitiglinide ((2 (S)-cis)-octahydro-gamma-oxo-alpha or N-methylmoranoline); and (6) Voglibose (3,4-dideoxy-4- (phenylmet-hyl)-2H-isoindole-2-butanoic acid, calcium salt, ((2-hydroxy-1-(hydroxymethyl)ethyl)amino)-2-C-(hy also known as mituglimide calcium hydrate, KAD 1229, or S droxymethyl)-D-epi-inositol or D-epi-lnositol.3,4-dideoxy 21403); (2) Ro 34563; (3) nateglinide (trans-N-(4-(1-meth 4-((2-hydroxy-1-(hydroxymethyl)ethyl)amino)-2-C- ylethyl)cyclohexyl) carbonyl)-D-phenylalanine, also known (hydroxymethyl)-, also known as A 71 100, AO 128, BASEN, as A 4166, AY 4166, YM 026, FOX 988, DJN 608, SDZ DJN608, STARLIX, STARSIS, FASTIC, TRAZEC); (4) JTT GLUSTAT, VOGLISTAT. 608 (trans-4-methyl-gamma-oxocyclohexanebutanoic acid); 0066 3. Insulins include regular or short-acting, interme (5) Sulfonylureas such as: (5a) chlorpropamide(1-(p-chlo diate-acting, and long-acting insulins, injectable, non-inject rophenyl)sulfonyl-3-propylurea, also known as DIAB able or inhaled insulin, transderamal insulin, tissue selective INESE); (5b) tolazamide(TOLINASE or TOLANASE); (5c) insulin, glucophosphokinin (D-chiroinositol), insulin ana tolbutamide(ORINASE or RASTINON); (5d) glyburide (1- logues such as insulin molecules with minor differences in the p-2-(5-chloro-o-anisamido)ethylphenylsulfon-yl-3-cy natural amino acid sequence and Small molecule mimics of clohexylurea, also known as Glibenclamide, DIABETA, insulin (insulin mimetics), and endoSome modulators. MICRONASE, GLYNASE PresTab, or DAONIL); (5e) glip Examples include, but are not limited to: (1) Biota; (2) LP izide (1-cyclohexyl-3-(p-2-(5-ethylpyrazinecarboxamido) 100: (3) (SP-5-21)-oxobis(1-pyrrolidinecarbodithioato-S, S") e-thylphenylsulfonylurea, also known as GLUCOTROL, Vanadium, (4) insulin aspart (human insulin (28B-L-aspartic GLUCOTROL XL, MINODIAB, or GLIBENESE); (5f) acid) or B28-Asp-insulin, also known as insulin X14, INA glimepiride (1H-pyrrole-1-carboxamide, 3-ethyl-2,5-dihy X14, NOVORAPID, NOVOMIX, or NOVOLOG); (5) insu dro-4-m-ethyl-N-(2-4-(4-methylcyclohexyl)aminocar lin detemir (Human 29B-(N6-(1-oxotetradecyl)-L-lysine)- bonylaminosulfonylphenyl-ethyl-2-oxo-, trans-, also (1A-21A), (1B-29B)-Insulin or NN 304); (6) insulin lispro known as Hoe-490 or AMARYL); (5g) acetohexamide (“28B-L-lysine-29B-L-proline human insulin, or Lys (B28), (DYMELOR); (5h) gliclazide (DIAMICRON); (5i) glipen Pro (B29) human insulin analog, also known as lys-pro insu tide (STATICUM); (5) gliquidone (GLURENORM); and lin, LY 275585, HUMALOG, HUMALOG MIX 75/25, or (5k) glisolamide (DIABENOR); (6) K" channel blockers HUMALOG MIX 50/50); (7) insulin glargine (human (A21 including, but not limited to, meglitinides such as (6a) Repa glycine, B31-arginine, B32-arginine) insulin HOE 901, also glinide (S)-2-ethoxy-4-(2-((3-methyl-1-(2-(1-piperidinyl) known as LANTUS, OPTISULIN); (8) Insulin Zinc Suspen phenyl)butyl)amino)-2-oxoethyl) benzoic acid, also known sion, extended (Ultralente), also known as HUMULINU or as AGEE 623, AGEE 623 ZW, NN 623, PRANDIN, or ULTRALENTE: (9) Insulin Zinc suspension (Lente), a 70% NovoNorm); (6b) imidazolines; and (6c) C-2 adrenoceptor crystalline and 30% amorphous insulin Suspension, also antagonists; (7) pituitary adenylate cyclase activating known as LENTE ILETINII, HUMULIN L, or NOVOLINL; polypeptide (PACAP); (8) vasoactive intestinal peptide (VIP); (10) HUMULIN 50/50 (50% isophane insulin and 50% insu (9) amino acid analogs; and (10) glucokinase activators. lin injection); (11) HUMULIN 70/30 (70% isophane insulin 0069. 6. Growth Factors such as: (1) insulin-like growth NPH and 30% insulin injection), also known as NOVOLIN factors (IGF-1, IGF-2); (2) Small molecule neurotrophins; (3) 70/30, NOVOLIN 70/30 PenFill, NOVOLIN 70/30 Prefilled; Somatostatin; (4) growth hormone-releasing peptide (12) insulin isophane suspension such as NPHILETIN II, (GHRP); (5) growth hormone-releasing factor (GHRF); and NOVOLINN, NOVOLINN PenFill, NOVOLINN Prefilled, (6) human growth hormone fragments. HUMULINN; (13) regular insulin injection such as ILETIN 0070 7. Immunomodulators such as: (1) vaccines; (2) II Regular, NOVOLIN R, VELOSULIN BR, NOVOLIN R T-cell inhibitors; (3) monoclonal antibodies; (4) interleukin-1 PenFill, NOVOLIN R Prefilled, HUMULIN R, or Regular (IL-1) antagonists; and (5) BDNF. U-500 (Concentrated); (14) ARIAD; (15) LY 197535; (16) 0071 8. Glucose resorption inhibitors such as those L-783281; and (17) TE-17411. described in U.S. Patent Application No. 2003/0045553. 0067. 4. Insulin secretion modulators such as (1) gluca 0072 9. Other antidiabetic agents: (1), Hu-Glucagon; (2) gon-like peptide-1 (GLP-1) and its mimetics; (2) glucose DHEA analogs; (3) carnitine palmitoyl transferase (CPT) insulinotropic peptide (GIP) and its mimetics; (3) exendin inhibitors; (4) islet neurogenesis; (5) pancreatic p amyloid and its mimetics; (4) dipeptyl protease (DPP or DPPIV) inhibitors; and (6) UCP (uncoupling protein)-2 and UCP-3 inhibitors such as (4a) DPP-728 or LAF 237 (2-pyrrolidin modulators. ecarbonitrile, 1-(((2-((5-cyano-1-2-pyridinyl)amino)ethyl) 0073. Additional agents ofuse in the invention include any amino)acetyl), known as NVP-DPP-728. DPP-728A, LAF agents known in the art for treatment of disorder of blood 237); (4b) P 3298 or P32/98 (di-(3N-((2S,3S)-2-amino-3- glucose regulations and/or their complications. Such agents methyl-pentanoyl-)-1,3-thiazolidine) fumarate); (4c) TSL include, but are not limited to, cholesterol lowering agents 225 (tryptophyl-1,2,3,4-tetrahydroisoquinoline-3-car such as (i) HMG-CoA reductase inhibitors (lovastatin, simv boxyli-c acid); (4d) Valine pyrrolidide (valpyr); (4e) 1-ami astatin and pravastatin, fluvastatin, atorvastatin, rivastatin, noalkylisoquinolinone-4-carboxylates and analogues pitavastatin, and other statins), (ii) sequestrants thereof (4f) SDZ 272-070 (1-(L-Valyl) pyrrolidine); (4g) (cholestyramine, colestipol and a dialkylaminoalkyl deriva TMC-2A, TMC-2B, or TMC-2C; (4h) Dipeptide nitriles tives of a cross-linked dextran), (iii) nicotinyl alcohol, nico (2-cyanopyrrolodides); (41) CD26 inhibitors; and (4) SDZ tinic acid or a salt thereof, (iv) PPAR.alpha. agonists such as 274-444; (5) glucagon antagonists such as AY-279955; and fenofibric acid derivatives (gemfibrozil, clofibrate, fenofi (6) amylin agonists which include, but are not limited to, brate and bezafibrate), (v) inhibitors of cholesterol absorption pramlintide (AC-137, Symlin, tripro-amylin or pramlintide for example beta-sitosterol and (acyl CoA:cholesterol acyl acetate). transferase) inhibitors for example melinamide and (vi) US 2008/0280955 A1 Nov. 13, 2008 probucol; PPARdelta agonists such as those disclosed in by any one of over 300 different mutations in a single gene. WO97/97/28149; antiobesity compounds such as fenflu Phenotypic changes may also result from variations in non ramine, dexfenfluramine, phentiramine, Sulbitramine, orl coding regions of the genome. For example, a single nucle istat, neuropeptide Y5 inhibitors, and, fadrenergic receptor otide variation in a regulatory region can upregulate or down agonist; and ileal bile acid transporter inhibitors. regulate gene expression or alter gene activity. 007.9 Technological developments in the field of human IV. Association Methods genomics have enabled the development of pharmacogenom 0074. In one aspect the invention provides methods of ics, the use of human DNA sequence variability in the devel identifying one or more genetic variations that at least partly opment and prescription of drugs. Pharmacogenomics is differentiate between a subset of a plurality of individuals based on the correlation or association between a given geno who experience a response, or are likely to experience a type and a resulting phenotype. Since the first association response, when administered a drug, e.g., an insulin sensi study over half-a-century ago linking adverse drug response tizer, and a subset of said plurality of individuals who do not with amino acid variations in two drug-metabolizing experience the response, or who are not likely to experience enzymes (plasma cholinesterase and glucose-6-phosphate the response, when administered the insulin sensitizer. In dehydrogenase), other correlation studies have linked some embodiments, the methods of the invention also include identifying one or more phenotypes that at least partly differ sequence polymorphisms in drug metabolism enzymes, drug entiate between the subset who experience or are likely to targets and drug transporters with compromised levels of experience a response when administered an insulin sensi drug efficacy or safety. Pharmacogenomics information is tizer, and the subset who do not experience or are not likely to especially useful in clinical settings where association infor experience the response when administered the insulin sen mation is used to prevent drug toxicities. For example, sitizer. The methods may also include predicting, based on patients may be screened for genetic differences in the thi one or more identified genotypes and/or phenotypes, whether opurine methyltransferase gene that cause decreased metabo a particular individual is predisposed to a response to an lism of 6-mercaptopurine or azathiopurine. insulin sensitizers 0080 Processes that may be used in specific embodiments 0075. A “response' to drug, e.g., an insulin sensitizer can of the methods herein are described in more detail in the be any response described herein, Such as a therapeutic following patent applications, all of which are specifically response or a non-therapeutic response (e.g., side effect, Such incorporated herein by reference: U.S. patent application Ser. as an adverse effect, as described herein). In some embodi No. 11/043,689, filed Jan. 24, 2005, entitled “Associations ments, the genetic variations are SNPs, in some of these Using Genotypes and Phenotypes: U.S. Provisional Appli embodiments, the SNPs include at least one informative SNP, cation Ser. No. 60/280,530, filed Mar. 30, 2001, entitled as described herein. In some embodiments the drug is an insulin sensitizer such as a thiazolidinedione PPAR modula “Identifying Human SNP Haplotypes, Informative SNPs and tor, for example, netoglitaZone. Uses Thereof: U.S. Provisional Application Ser. No. 60/313, 0076 Although the association methods described herein 264 filed Aug. 17, 2001, entitled “Identifying Human SNP are Suitable for use with any drug, for convenience in some Haplotypes, Informative SNPs and Uses Thereof: U.S. Pro details are described interms of insulin sensitizers. It is under visional Application Ser. No. 60/327,006, filed Oct. 5, 2001, stood that this is for convenience only, and that any drug may entitled “Identifying Human SNP Haplotypes, Informative be studied by these methods. The methods utilize techniques SNPs and Uses Thereof: U.S. Provisional Application Ser. of genomics and, in particular, pharmacogenomics. No. 60/332,550, filed Nov. 26, 2002, entitled “Methods for 0077. As used herein, the terms “differentiate at least in Genomic Analysis”; U.S. application Ser. No. 10/106,097, part and “at least partly differentiate’ mean a clinically filed Mar. 26, 2002, entitled “Methods for Genomic Analy useful result that can be used to differentiate cases from sis”; U.S. Pat. No. 6,897,025, issued May 24, 2005, entitled controls and is at least about 50% sensitive, or at least about “Genetic Analysis Systems and Methods”; and U.S. applica 60% sensitive, or at least about 70% sensitive, or at least about tion Ser. No. 10/284,444, filed Oct. 31, 2002, entitled 80% sensitive, or at least about 90% sensitive, or at least about “Human Genomic Polymorphisms’. U.S. Provisional Patent 95% sensitive, or at least about 99% sensitive; or a clinically Application No. 60/648,957, filed Jan. 31, 2005, entitled useful result that can be used to differentiate cases from “Compositions and Methods For Treating, Preventing, and controls and is at least about 50% specific, or at least about Diagnosing Alzheimer's Disease. U.S. application Ser. No. 60% specific, or at least about 70% specific, or at least about 10/956.224, filed Sep. 30, 2004, entitled “Methods for genetic 80% specific, or at least about 90% specific, or at least about analysis. U.S. Provisional Patent Application No. 60/653, 95% specific, or at least about 99% specific. 672, filed Feb. 16, 2005, entitled “Parkinson's Disease-Re 0078. The DNA that makes up human chromosomes pro lated Disease Compositions and Methods.” U.S. application vides the instructions that direct the production of all proteins Ser. No. 10/768,788, filed Jan. 30, 2004, entitled “Apparatus in the body. These proteins carry out vital functions of life. and Methods for Analyzing and Characterizing Nucleic Acid Variations in DNA are directly related to almost all human Sequences.” U.S. application Ser. No. 10/351,973, filed Jan. diseases, including infectious diseases, cancers, inherited dis 27, 2003, entitled “Apparatus and Methods for Determining orders, and autoimmune disorders. Variations in DNA con Individual Genotypes.” U.S. application Ser. No. 10/970,761, tributing to a phenotypic change. Such as a disease or a dis filed Nov. 20, 2004, entitled “Improved Analysis Methods order, may result from a single variation that disrupts the and Apparatus for Individual Genotyping. U.S. application complex interactions of several genes or from any number of Ser. No. 10/786,475, filed Feb. 24, 2004, entitled “Analysis mutations within a single gene. For example, Type I and II Methods for Individual Genotyping,” and U.S. Provisional diabetes have been linked to multiple genes, each with its own Patent Applications No. 60/643,006, 60/635,281 filed Jan. 11, pattern of mutations. In contrast, cystic fibrosis can be caused 2005, and Dec. 9, 2004, respectively, both entitled “Markers US 2008/0280955 A1 Nov. 13, 2008

for Metabolic Syndrome Obesity and Insulin Resistance the may be referred to herein as “rare SNPs, and haplotype disclosures all of which are specifically incorporated herein patterns and allelic variations that have a frequency of less by reference. than 10% in the population may be referred to herein “rare 0081 Sequencing the human genome has revealed that haplotype patterns” and “rare allelic variations.” respectively. there is a high degree of homology in genetic information 0.086 Table 1 below illustrates nucleotide bases in six between individuals. In particular, any two humans share positions in a DNA molecule from three individuals. The approximately 99.9% the same DNA sequence and have up to nucleotide base positions can be in genomic DNA or RNA (U about 20,000 to about 30,000 or so genes similarly situated in replaces T in RNA). one of twenty-three chromosomes. However, genomic varia tions between any two individuals still exist. For example, TABLE 1 approximately 0.1%, or one out of every 1,000 DNA letters, is variable in a population of humans. Nucl. Position: 0082 Genetic variations between individuals can occur in 1 2 3 4 5 6 many forms. Examples of genetic variations include, but are not limited to, deletions or insertions of one or more nucleic Individual 1: T A. G T C G acids, variations in the number of repetitive DNA elements, Individual 2: T A. A T C C and changes in a single nitrogenous base position, also known Individual 3: T A. G T C G as “single nucleotide polymorphisms' or “SNPs. It is noted that any of the genetic variations herein can appearin DNA as I0087. At nucleotide positions 1-2 and 4-5, all three indi well as RNA. viduals have the same nucleotide bases. At nucleotide posi 0083 SNPs that may be used in the methods and compo tions 3 and 6, individual 2 has SNP alleles represented by sitions of the invention include those described in Hinds et al. underlined nucleotide bases A and C, respectively, as com (2005) Science 307:1072-1079 and available at genome-per pared with individuals 1 and 3 who have SNP alleles G and G legen.com; research.calit2.net/hep/wgha/; hapmap.org; Sci at the same nucleotide positions. encemag.org/cgi/content/full/307/5712/1072/DC1: dbSNP; I0088. If both major and minor alleles of SNPs found at and genewindow.nci.nih.gov. positions 3 and 6 have an allele frequency of at least about 0084. It is estimated that there are 3-4 million common 10% in the population (e.g., major and minor SNP alleles SNPs. Typically, SNPs are biallelic, which means that they occur at a ratio of 90% and 10%, or 70% and 30%, but not occur in two forms, a major allele and a minor allele, with the 95% and 5%, respectively), then such SNPs are referred to as major allele being more frequently observed than the minor common SNPs. Furthermore, if the two SNP alleles (e.g., A allele. Typically, the major allele occurs in more than 50% of and C) at positions 3 and 6 consistently appear together (i.e., the population; while the minor allele occurs in less than 50% are in linkage disequilibrium with one another), then they are of the population. Common SNPs are those SNPs that have a part of a haplotype pattern. A haplotype pattern refers to minor allele frequency of at least about 10%, meaning that genotyped SNP alleles that appear together more frequently within a given population the minor allele is present at the than expected by chance. The SNP locations of the SNP SNP locus at least about 10% of the time. Furthermore, com alleles in a haplotype pattern form a haplotype block. Haplo mon SNPs do not occur independently but are inherited type blocks can include known as well as currently unknown together from generation to generation in genetic disequilib SNPs. A SNP whose genotype is predictive of a genotype of rium with other SNPs, forming patterns across genomic DNA one or more other SNPs in a haplotype block is often referred and RNA. Groups of SNPs that are in linkage disequilibrium to as an “informative SNP. For purposes of conducting asso with one another define genomic regions that are referred to ciation studies to predict a phenotype-of-interest, it may be herein as haplotype blocks. Sufficient to Scan only one, only two, or only a few informa I0085. The term “haplotype block” as used herein refers to tive SNPs from one or more haplotype blocks. a region of a chromosome that contains one or more poly I0089. In some embodiments, the present invention con morphic sites (e.g., 1-10) that tend to be inherited together templates Scanning an initial set of nucleotide bases from a (i.e., are in linkage disequilibrium) (see Patil, et al., Science, plurality of individuals to identify one or more genetic varia 2.94:1719-1723 (2001); US 20030186244)) or that are tions (e.g., common SNPs). Such a scanning step can occur together associated with a phenotypic trait of interest. In other prior to, contemporaneous with, or after receiving data on the words, combinations of polymorphic forms at the polymor set of phenotypes for such individuals that are selected for an phic sites within a block cosegregate in a population (e.g., association study, i.e., responsiveness to an insulin sensitizer, with a phenotypic trait of interest) more frequently than com where the response may be a therapeutic response or a non binations of polymorphic sites that occur in different haplo therapeutic response, e.g., a side effect such as an adverse type blocks. In some embodiments, adjacent haplotype effect. This initial set of bases can come from the same and/or blocks do not overlap one another (i.e., are “nonoverlap different individuals as those selected for the association ping). In some embodiments, a haplotype block may also be study. a linkage disequilibrium bin (see Hinds, et al., Science, 307: 0090. In some cases a surrogate marker is used as an 1072-1079 (2005)). A haplotype block is further character indication of a response to a drug, e.g., insulin sensitizer. Such ized by one or more haplotype patterns. A haplotype patternis markers are well-known in the art and are typically chosen for the set of SNP alleles on a single nucleic acid strand within a their ease of measurement, and often because they indicate a single haplotype block (e.g., on a single chromosome of a therapeutic or non-therapeutic effect before such an effect single individual). SNP alleles, haplotype patterns, and allelic becomes apparent from clinical observation. An example is variations that do not have a frequency of at least about 10% the use of blood lipid levels or ratios as markers for potential in a given population can be described as rare. Therefore, adverse (or therapeutic) cardiovascular effects. Any suitable SNPs with a minor allele frequency of less than about 10% Surrogate marker may be used in the methods of the invention. US 2008/0280955 A1 Nov. 13, 2008

One useful marker is levels of expression of proteins coded about 10,000 bases, at least about 20,000 bases, at least about for by genes involved in the disorder being treated; increases 50,000 bases, at least about 100,000 bases, at least about and/or decreases in protein expression levels and ratios of 200,000 bases, at least about 500,000 bases, at least about expression of certain proteins can be useful and powerful 1,000,000 bases, at least about 2,000,000 bases, at least about indicators of therapeutic or non-therapeutic effects. Methods 5,000,000 bases, at least about 10,000,000 bases, at least for determining protein expression levels are well-known in about 20,000,000 bases, at least about 50,000,000 bases, at the art. least about 100,000,000 bases, at least about 200,000,000 0091 Methods for identifying genetic variations are bases, at least about 500,000,000 bases, at least about 1,000, known in the art. For example, the identity of SNPs and SNP 000,000 bases, at least about 2,000,000,000 bases, or at least haplotype blocks across one representative chromosome about 3,000,000,000 bases, or substantially all of an individu (e.g., Chromosome 21) are disclosed in U.S. Provisional al’s genetic material. Serial No. 60/323,059, filed Oct. 31, 2002, entitled “Human 0097. In some embodiments, a scanning step or diagnostic Genomic Polymorphisms' assigned to the assignee of the tool that identifies or genotypes genetic variations scans less present invention; and U.S. application Ser. No. 10/284.444, than 100,000,000 bases, less than 50,000,000 bases, less than filed Oct. 31, 2002, entitled “Human Genomic Polymor 10,000,000 bases, less than 5,000,000 bases, less than about phisms, incorporated herein by reference for all purposes. 3,000,000,000 bases, less than about 2,000,000,000 bases, See also Patil, N. et al., “Blocks of Limited Haplotype Diver less than about 1,000,000,000 bases, less than about 500,000, sity Revealed by High-Resolution Scanning of Human Chro 000 bases, less than about 200,000,000 bases, less than about mosome 21 '' Science 294, 1719-1723 (2001), disclosing 100,000,000 bases, less than about 50,000,000 bases, less SNPs and haplotype structure of Chromosome 21. than about 20,000,000 bases, less than about 10,000,000 0092. In some embodiments, whole genome analysis is bases, loess than about 5,000,000 bases, less than about performed to identify genetic variations across the entire 2,000,000 bases, less than about 1,000,000 bases, less than genome (DNA and/or RNA). Methods for whole genome about 500,000 bases, less than about 200,000 bases, less than analysis can be used both to identify known and/or new varia about 100,000 bases, less than about 50,000 bases, less than tions. Such methods are described in U.S. Provisional Appli about 20,000 bases, less than about 10,000 bases, less than cation No. 60/327,006, filed Oct. 5, 2001, entitled “Identify about 5,000 bases, less thanabout 2,000 bases, less than about ing Human SNP Haplotypes, Informative SNPs and Uses t 1,000 bases, less than about 500 bases, less than about 200 Thereof, and U.S. Pat. No. 6,969,589, both of which are bases, less than about 100 bases, less than about 50 bases, less assigned to the assignee of the present invention, all of which than about 20 bases, or less than about 10 bases. are incorporated herein by reference for all purposes. Addi 0.098 Scanning nucleotide bases in a first set of individu tional descriptions of genome analysis, i.e., methods of als (e.g., at least about 10 individuals, at least about 20 indi sequencing, are suggested in U.S. Pat. Nos. 6,767,706; 6,818, viduals, at least about 30 individuals, at least about 40 indi 395; 6,833,242; 6,344,325; and 6,221,654, all of which are viduals, or at least about 50 individuals) allows for incorporated herein by reference for all purposes. identification of new genetic variations and/or genetic varia 0093 Briefly, in order to scan full genomes, full sets of tions between individuals. Genetic variation data generated chromosomes may be separated from samples from individu from each individual e.g. is compared with genetic variation als (e.g., more than 10, more than 20, more than 30, more than data generated from other individuals in the first set of indi 40, or more than 50 individuals). This results in multiple viduals in order to discover 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more unique genomes. In some embodiments, haploid genomes (or or 10, 20, 30, 40, 50, 60, 70, 80, 90, 100 or more or 1,000, genomes derived from a single set of chromosomes) are used. 5,0000, 100,000, 500,000, 1,000,000 or more, or substan 0094. In some embodiments, RNA (e.g. mRNA) may be tially all or all genetic variations among the first group of scanned to identify genetic variations. In order to scan RNA, individuals. RNA is first isolated from a cell, group of cells, or individuals. 0099. The variations identified in the first set of individu Methods for isolating RNA are known in the art. RNA can be als can be used in Subsequent association studies in which isolated from more than 10, more than 20, more than 30, more Such variations are analyzed to determine if they are associ than 40, or more than 50 individuals. Differences in expres ated with a phenotype-of-interest. These variations include, sion patterns and/or genetic variations in RNA can be identi e.g., SNPs, common SNPs, informative SNPs, rare SNPs, fied using any means known in the art or disclosed herein. See deletions, insertions, frameshift mutations, etc. Such genetic e.g. U.S. application Ser. Nos. 10/438,184 and 10/845,316, variations can be detected in, for example, genomic DNA, and PCT/US/04/010699, which are incorporated herein by RNA, mRNA, or derivatives thereof. In some embodiments, reference for all purposes. genetic variations scanned and/or identified are informative 0095. In some embodiments, all or a significant portion of SNPs. Identification of informative SNPs can reduce the cost an individual's genetic material (e.g., DNA, RNA, mRNA, and increase the efficiency of association studies because the cDNA, other nucleotide bases or derivative thereof) is genotype of a single informative SNP can predict the geno scanned or sequenced using, e.g., conventional DNA type of one or more other SNP locations. Further descriptions sequencers or chip-based technologies to identify a set of of informative SNP and use thereofare further discussed in: SNPs and their corresponding alleles. In some embodiments, U.S. Provisional Application Ser. No. 60/280,530, filed Mar. whole-wafer technology from Affymetrix, Inc. of Santa 30, 2001, entitled “Identifying Human SNP Haplotypes, Clara, Calif. is used to read each individual's genome and/or Informative SNPs and Uses Thereof: U.S. Provisional RNA at single-base resolution. Application Ser. No. 60/313.264 filed Aug. 17, 2001, entitled 0096. A scanning step or diagnostic tool (whether to iden “Identifying Human SNP Haplotypes, Informative SNPs and tify new genetic variations or to genotype an individual) can Uses Thereof: U.S. Provisional Application Ser. No. 60/327, involve scanning at least about 1 base, at least about 10 bases, 006, filed Oct. 5, 2001, entitled “Identifying Human SNP at least about 100 bases, at least about 1000 bases, at least Haplotypes, Informative SNPs and Uses Thereof: U.S. Pro US 2008/0280955 A1 Nov. 13, 2008

visional Application Ser. No. 60/332,550, filed Nov. 26, 2002, 475, filed Feb. 24, 2004, entitled “Improvements to Analysis entitled “Methods for Genomic Analysis”; U.S. Pat. No. Methods for Individual Genotyping”; U.S. Ser. No. 10/970, 6,969,589; and U.S. application Ser. No. 10/284.444, filed 761, filed Oct. 20, 2004, entitled “Analysis Methods and Oct. 31, 2004, entitled “Human Genomic Polymorphisms.” Apparatus for Individual Genotyping, U.S. application Ser. all of which are incorporated herein by reference for all pur No. 10/427,696, filed Apr. 30, 2003, entitled Method for poses. Identifying Matched Groups. U.S. application Ser. No. 0100 For example, in conducting whole genome associa 10/768,788, filed Jan. 30, 2004, entitled Apparatus and Meth tion studies, instead of scanning and reading all 3 billion ods for Analyzing and Characterizing Nucleic Acid bases from each genome or about 3 to 4 million common Sequences.” and in U.S. application Ser. No. 10/956.224, SNPs, it is possible to scan or read simply about 200,000 to filed Sep. 30, 2004, entitled “Methods for Genetic Analysis’, 500,000 informative (or “tag”) SNPs, which may provide a all of which are incorporated herein by reference for all pur majority of the information as would scanning the entire poses. genome (Hinds, et al., Science, 307:1072-1079 (2005)). Thus, while in Some embodiments the present invention con 0103) To increase efficiency of collecting genotyping data, templates Scanning whole genomes for association studies, in cases and/or controls can be pooled prior to scanning as is other embodiments only specific chromosomes, genomic described in U.S. application Ser. No. 10/447,685, filed May regions, SNPs, common SNPs, or informative SNPs are 28, 2003, entitled “Liver Related Disease Compositions and scanned (e.g., genotyped) and/or used to conduct association Methods”, U.S. application Ser. No. 10/427,696; filed Apr. studies. Specific chromosomes, genomic regions, SNPs, 30, 2003; entitled “Methods for Identifying Matched common SNPs, or informative SNPs may be selected for Groups'; and 10/768,788; filed Jan. 30, 2004; entitled “Appa association studies based on prior knowledge that Such ratus and Methods for Analyzing and Characterizing Nucleic regions are or may be related to a particular phenotype-of Acid Sequences” which are incorporated herein by reference. interest (e.g., disease state or lack thereof). For example, they For example, Samples obtained from all or some case indi may have been previously identified in other association stud viduals may be pooled together prior to Scanning and/or all or ies (e.g., linkage disease mapping studies) or based on homol samples from all or some control individuals may be pooled ogy with genes of known function. together separately (pool of cases and pool of controls) prior 0101 Thus, in some embodiments the methods of the to Scanning. In another example, data on genetic variations invention utilize known SNPs, available from databases and/or phenotypes from some or all case individuals and/or herein or from any suitable source known in the art. In these some or all control individuals may be pooled together. Fur embodiments, it is not necessary to scan the entire genome. In thermore, in any of the embodiments herein, genetic variation Some embodiments, known sites of genetic variation, e.g., data collected can be stored in a computer readable medium SNPs, are scanned. These embodiments can involve genotyp for further analysis. ing less than about 15,000; 200,000: 500,000; 1,000,000; 0104. In any of the embodiments herein, a scanning step 2,000,000, or substantially all genetic variations of an indi (for either identifying or genotyping variations) may be vidual. In some embodiments, known sites of genetic varia Supplemented and/or substituted by receiving data on the tion, e.g., SNPs, are scanned. These embodiments can involve genetic variations from database(s). Such databases can pro genotyping at least about 10,000; 100,000: 500,000; 1,000, vide, for example, a list of identified genetic variations (e.g., 000; 2,000,000; or substantially all genetic variations of an SNPs or haplotypes) or genotyping data on particular indi individual. In some embodiments, about 1 to about 10, about viduals. Examples of publicly available databases that iden 10 to about 100, about 100 to about 1000, about 1000 to about tify genetic variations include, but are not limited to, genome. 10,000, about 10,000 to about 100,000, about 10,000 to about perlegen.com; research.calit2.net/hep/wgha/; hapmap.org; 1,000,000, about 10,000 to about 2,000,000, or about 100,000 sciencemag.org/cgi/content/ful/307/5712/1072/DC1; to about 2,000,000, or about 500,000 to about 2,000,000, or genewindow.nci.nih.gov. NCBI's dbSNP (ncbi.nlm.nih.gov/ about 1,000,000 to about 2,000,000, or about 10,000 to about SNP/index.html); MIT’s human SNP database (broad.mit. 1,000,000, or about 10,000 to about 500,000, or about 10,000 edu/snp/human/); University of Geneva's human Chromo to about 100,000, or about 100,000 to about 2,000,000, or some 21 SNP database (csimp.unige.ch/). and the University of about 100,000 to about 1,000,000, or about 100,000 to about Tokyo’s SNP database (snp.ims.u-tokyo.ac.jp/). Other data 500,000 genetic variations in an individual are genotyped. bases known in the art may be used in conjunction with the 0102 The present invention contemplates association methods herein. studies using genetic variations and phenotypes of individu 0105. In some embodiments, described herein, the present als from both case and control groups. Case group individuals invention contemplates the use of one or more genetic varia are those who express a phenotype-of-interest, e.g., respon tions between individuals (e.g., SNP alleles, and haplotype siveness to drug such as an insulin sensitizer, where the patterns) in association studies to predict if an individual has responsiveness may be therapeutic or non-therapeutic or does not have responsiveness to an insulin sensitizer. In response. Control group individuals are those who do not other embodiments, the present invention contemplates using express the phenotype-of-interest, i.e., who do not exhibit phenotypic variations in addition to genotypic variations in responsiveness to an insulin sensitizer. In some embodi association studies. Association studies using only genetic ments, a case group includes at least 2, 5, 10, 20, 50, 100, 200, variations are described in U.S. application Ser. No. 10/447. 500, or 1000 individuals and a control group includes at least 685, filed May 28, 2003, entitled “Liver Related Disease 2, 5, 10, 20, 50, 100, 200, 500, or 1000 individuals. Methods Compositions and Methods’. U.S. Provisional Patent Appli for performing genotype association studies using case and cation No. 60/648,957, filed Jan. 31, 2005, entitled “Compo control groups are described, e.g., in U.S. Ser. No. 10/351, sitions and Methods For Treating, Preventing, and Diagnos 973, filed Jan. 27, 2003, entitled “Apparatus and Methods for ing Alzheimer's Disease, and U.S. Provisional Patent Determining Individual Genotypes: in U.S. Ser. No. 10/786, Application No. 60/653,672, filed Feb. 16, 2005, entitled US 2008/0280955 A1 Nov. 13, 2008

“Parkinson's Disease-Related Disease Compositions and Ser. No. 10/284,444, entitled “Chromosome 21 SNPs, SNP Methods', which are incorporated herein by reference. Groups and SNP Patterns.” filed on Oct. 31, 2002, assigned to 0106 Association studies using genetic variations and the same assignee as the present application; and U.S. Pat. phenotypic variations are described in U.S. patent application No. 6,897,025, entitled “Genetic Analysis Systems and Meth Ser. No. 11/043,689, filed Jan. 24, 2005, entitled “Associa ods.’ issued on May 24, 2005, assigned to the same assignee tions Using Genotypes and Phenotypes; which is incorpo as the present application, all of which are incorporated rated herein by reference. Like genotyping data, data on a set herein by reference. The microarrays are manufactured using of phenotypes of the individuals is received for both case a process adapted from semiconductor manufacturing to individuals and control individuals. The data on a set of phenotypes can include data on at least about 1, 2, 3, 4, 5, 6, achieve cost effectiveness and high quality. 7, 8, 9, or 10 different phenotypes, or on at least about 10, 25, 0110 Variants identified are grouped into haplotype 30, 35, 40, 45 or 50 different phenotypes of the individuals in blocks using methods disclosed in U.S. Pat. No. 6,969,589, the association study. The data on the set of phenotypes can be incorporated herein by reference. Representative variants and collected prior to, Subsequent to, or simultaneous with the haplotype blocks from an entire human chromosome (chro collection?gathering of genotyping data. Phenotype data col mosome 21) are disclosed in, for example, U.S. application lected can (like the genotyping data) also be stored in a Ser. No. 10/284.444, filed Oct. 31, 2002, entitled “Human computer readable medium for further use. Genomic Polymorphisms'; and Patil, N. et al., “Blocks of Limited Haplotype Diversity Revealed by High-Resolution A. Genotyping Data Scanning of Human Chromosome 21 Science 294, 1719 0107 An association study may be performed to identify 1723 (2001) and the associated supplemental materials, genetic loci associated with responsiveness to a drug, e.g., to incorporated herein by reference. an insulin-sensitizing drug. A two-stage approach can be used 0111 Case samples are obtained from individuals who in which, first, pooled sample sets are used to identify genetic have demonstrated responsiveness when given the drug, e.g., regions that may be associated with the trait of interest. While insulin sensitizer. Individuals are evaluated clinically. A actual allele frequency differences between the case and con “response' is as described herein, and can be a therapeutic trol sample pools cannot be measured in these sample sets, response or a non-therapeutic response. Non-therapeutic allele frequency differences may be estimated, and used to responses include adverse effects, including, but not limited select a subset of SNPs for further evaluation. This subset, to (in the case of insulin sensitizers) peripheral edema, depen which may have contained false positives in addition to true dent edema, generalized edema, weight increase, anemia, positives, is then genotyped in the individual case and control hypoglycemia, headache, increase in micturation frequency, samples, and the exact allele frequency differences between diarrhea, increased appetite, transient ischemic attack, the populations are calculated. In some embodiments, the elevated liver enzymes, and combinations thereof. Control population that is individually genotyped is the same as the samples are obtained from individuals who have not demon population Subjected to pooled genotyping; in other embodi strated the same responsiveness as the case individuals when ments, the population that is individually genotyped is differ given the drug, e.g., insulin sensitizer, controls and cases have ent from the population Subjected to pooled genotyping; in different responses, e.g., one may have low efficacy and the still other embodiments, individual genotyping may be per other high efficacy, etc. Criteria for inclusion in the case and formed both on the population that was subjected to pooled control groups are determined prior to the commencement of genotyping as well as at least one additional population. In the study. Some embodiments, the pooled populations for cases and for 0112 Pooled genotyping Arrays are designed to assay for controls can be matched with regard to population structure in all or a subset of the total SNPs of the genome. Any subset order to reduce variation not associated with the phenotype(s) may be used that produces meaningful data; for example, of interest. Such an analysis may also be performed after numerous publicly available databases describe subsets of pooling to verify that the populations are matched. Methods SNPs in the human genome and are available, e.g., as of matching populations may be found in, e.g. Hinds, D. A. et described elsewhere herein. al. Matching strategies for genetic association studies in 0113 Oligonucleotide arrays are designed such that each structured populations. Am J Hum Genet 74, 317-25 (2004), SNP is interrogated by a set of probes. For example, in some U.S. patent application Ser. No. 10/427,696, filed Apr. 30, embodiments an array may be designed so that each SNP is 2003, entitled “Method for Identifying Matched Groups, and interrogated by, e.g., forty distinct 25bp probes. These forty Bacanu, S.A., etal. The power of genomic control. Am J Hum features consist of four sets often features, corresponding to Genet 66, 1933-44 (2000), all of which are incorporated by the forward and reverse strands of the two SNP alleles (ref. reference herein in their entirety. erence and alternate). Each set often features consists of two 0108. In some embodiments, a third stage may be per sets offive features, with offsets of -2, -1, 0, +1, and +2 bases formed in which SNPs showing significant association with between the center of the 25bp probe and the SNP position. susceptibility (or resistance) to adverse effects of insulin For each offset, one perfect-match feature and one mismatch sensitizing drugs in the original sample set are then analyzed feature (complement of the perfect match at the interrogation in a one or more additional sample sets, in order to Verify or position only) are tiled at the central position of the probe. validate their association. These studies are referred to as Thus, for each allele there is a total of ten perfect-match validation studies. probes and ten mismatch probes. The oligonucleotide fea 0109 The human genome is scanned to identify or geno tures necessary to query the SNPs are arrayed on one or more type genetic variants using microarray technology platforms distinct array designs. See: U.S. application Ser. No. 10/970, such as described in U.S. Pat. No. 6,586,750, entitled “High 761, filed Oct. 20, 2004, entitled “Improved Analysis Meth Performance Substrate Scanning, U.S. Pat. No. 6,969,589, ods and Apparatus for Individual Genotyping for further assigned to the same assignee as the present application; U.S. description. US 2008/0280955 A1 Nov. 13, 2008

0114 Samples can be analyzed for quality, e.g., as fol mates of allele frequency, p-hat, are computed from ratios of lows: (1) concentration and Volume are measured to make trimmed means of intensities of the perfect-match features, Sure that they match the expected values, and are adequate for after Subtracting a measure of background computed from the study; (2) gel electrophoresis is performed on a Subset of trimmed means of intensities of mismatch features. The case samples to examine DNA integrity; and (3) PCR assays are pool p-hats and control pool p-hats are separately averaged, performed to establish the ability of the DNA samples, or a and the deltap-hat is calculated. Finally, the standard error of subset thereof, to be amplified. the estimate, based on the within pool variance of the mea 0115. After passing QC the samples are diluted to an Surements, t-statistic p-value, and empirical p-values (which appropriate concentration, and re-quantified. The samples were obtained as rank of T TEST P VALUE on each chip can be divided into pools in any Suitable manner. In any given design divided by the total number of passing SNP measure pooled analysis, the samples may be pooled in Such a manner ments for each chip design) for the deltap-hat are calculated as to provide the desired information regarding genotype for each of the SNPs that passed the QC filters. See, e.g., U.S. and/or variations due to sample handling. In some embodi Ser. No. 10/768,788, filed Jan. 30, 2004, entitled “Apparatus ments, cases and controls may each be divided into individual and Methods for Analyzing and Characterizing Nucleic Acid pools, and each individual pool can be analyzed. The number Sequences.” of pools may be one, two, three, four, five, six, seven, eight, 0118. The following quality control filters can be applied nine, ten, or more than ten. For example, the samples may be to the data to assess the reliability of the fluorescence inten divided into a total of, e.g., eight pools, four containing case sities of the features for each SNP in an array scan. Applying samples and four containing control samples. Thus, each pool these filters, which are based on findings from numerous contains, e.g., 100 samples, randomly selected from either the previous association studies, increases the quality of the pass cases or controls, with each sample present injust one pool. ing SNPs, thereby reducing false-positive associations. SNP Equimolaramounts of each sample are transferred into one of measurements are removed from consideration if they had the eight pools. Each pool may then be re-quantified and any of the following: (1) conformance of <0.9; (2) saturated diluted to a standard concentration for use as a PCR template. probes; and (3) signal-to-background ratio of <1.5. U.S. Alternatively, in some embodiments, replicate pools, each of application Ser. No. 10/970,761, filed Oct. 20, 2004, entitled which consists of the same Subset of the cases or controls may “Improved Analysis Methods and Apparatus for Individual be analyzed. The number of pools may be one, two, three, Genotyping has further descriptions of the implementation four, five, six, seven, eight, nine, ten, or more than ten. For of these quality measures. example, the samples may be divided into a total of, e.g., eight 0119 The conformance of alleles is defined as the fraction pools, four containing case samples and four containing con offeature pairs for which the perfect-match feature is brighter trol samples. Thus, each pool contains, e.g., 100 samples, than the corresponding mismatch feature. A conformance of randomly selected from either the cases or controls, but in this <0.9 can indicate the absence of target DNA. Both saturated embodiment, each sample is present in each of the four case probes and low signal-to-background ratios can lead to unre pools or in each of the four control pools. Equimolar amounts liable p-hat measurements. of each sample are transferred into one of the eight pools. 0.120. In some embodiments, SNPs are selected for further Each pool may then be re-quantified and diluted to a standard evaluation (individual genotyping) if they pass other criteria, concentration for use as a PCR template. The latter embodi such as threshold for p-values for the delta p-hat measure ment allows the study of variations introduced by the proce ments, standard error (SE) of delta p-hat measurements, and dures used in analysis. In other embodiments, aliquots of all other QC filters. In addition, individual genotyping may also the case samples may be present in more than one “case pool.” include SNPs not amplified in the pooled genotyping phase; and aliquots of all the control samples may be present in more SNPs to control for population stratification (see, e.g., U.S. than one “control pool.” patent application Ser. No. 10/427,696, filed Apr. 30, 2003, 0116. The pools are independently amplified using, e.g., entitled “Method for identifying matched groups”); and/or multiplexed PCR with a single primer pair for each SNP. The SNPs from candidate regions. amplified products are pooled, labeled and hybridized to the chip or chips that individually or together query the set of Individual Genotyping SNPs selected for genotyping. The hybridized chips are SNPs Genotyped in Individual Samples washed and stained. The hybridization of labeled sample is detected. See, e.g., U.S. Ser. No. 1 1/344.975, filed Jan. 31, I0121 Selected SNPs are individually genotyped in each of 2006, entitled "Genetic Basis of Alzheimer's Disease and the case and control samples. These can include SNPs Diagnosis and Treatment Thereof.” U.S. Ser. No. 1 1/299,298, selected on the basis of the pooled genotyping results, SNPs filed Dec. 9, 2005, entitled “Markers for Metabolic Syndrome from the candidate regions, and SNPs to control for popula Obesity and Insulin Resistance.” and U.S. Ser. No. unas tion stratification. The case and control samples that are indi signed, docket no.300/1081-10, filed Sep. 27, 2006, entitled vidually genotyped may be the same as or different from “Genetic Basis of Rheumatoid Arthritis and Diagnosis and those that were Subjected to pooled genotyping. Treatment Thereof.” High-Density Oligonucleotide Arrays 0117. After removing SNP measurements that fail quality control (see below), the estimated allele frequency difference 0122. A new array can be designed to individually geno between case and control pools, termed delta p-hat, is auto type the selected SNPs, such that all selected SNPs can be matically derived for each SNP from intensity ratios for assayed using a single chip for each individual DNA sample. hybridization to the allele-specific 25-mer features. The fluo rescence intensities of the reference and alternate perfect Individual Genotyping of Case and Control Samples match features on the arrays correlate with the concentration I0123. The SNPs from the case and control samples are of the corresponding SNP allele in the DNA sample. Esti amplified. The amplified samples from each individual are US 2008/0280955 A1 Nov. 13, 2008 pooled and hybridized to oligonucleotide arrays, thereby que entitled “Algorithm for Estimating Accuracy of Genotype rying each SNP for only one individual in each pooled Assignment, the disclosures of which are incorporated by sample. In addition, the samples may be pooled prior to being reference in their entireties. amplified. The hybridized chips are washed and stained, and the resulting fluorescence detected as for the pooled genotyp Individual Genotyping Results ing. Assessing the False-Positive and False-Discovery Rates 012.4 Methods for individual genotyping are detailed, 0.126 The number of SNPs with significant trend test e.g., in U.S. Ser. No. 10/351,973, filed Jan. 27, 2003, entitled p-values that would be expected to be found purely by chance Apparatus and Methods for Determining Individual Geno can be calculated, assuming no enrichment of large allele types.” U.S. Ser. No. 10/786,475, filed Feb. 24, 2004, entitled frequency differences in the pooling phase of the study. The Analysis Methods for Individual Genotyping. U.S. Ser. No. expected value may be compared with the actual number, and 10/970,761, filed Oct. 20, 2004, entitled “Analysis Methods if the number of observed SNPs below each of the different and Apparatus for Individual Genotyping, and U.S. Ser. No. p-value cutoffs is greater than the expected number, then the 11/173,809, filed Jul. 1, 2005, entitled “Algorithm for Esti pooled genotyping did indeed enrich the SNP set for SNPs mating Accuracy of Genotype Assignment. In certain with large allele frequency differences. False discovery rates embodiments, individual genotypes for each SNP are deter may also be calculated as the ratio of the expected number of mined by clustering the intensity measurements of all false positives to the number of observed SNPs with signifi samples, in the two-dimensional space defined by back cant trend test p-values below a certain cutoff. ground-adjusted trimmed mean intensities of the perfect I0127 Thus, using high density array technology, SNPs match features for the reference and alternate alleles. See U.S. associated with susceptibility to one or more adverse effects application Ser. No. 10/970,761, filed Oct. 20, 2004, entitled of a drug or class of drugs are identified by measuring SNP “Improved Analysis Methods and Apparatus for Individual allele frequency differences between cases and controls. In Genotyping; Hinds, D. A. et al. Matching strategies for some embodiments, all or substantially all of the SNPs thus genetic association studies in structured populations. Am J identified may be used in other studies or in the clinical setting Hum Genet 74,317-25 (2004); Hinds, D. A. et al. Application to predict a response or non-response to an insulin sensitizer. of pooled genotyping to scan candidate regions for associa In some embodiments, a subset of the SNPs thus identified tion with HDL cholesterol levels. Human Genomics 1, 421 may be used in other studies or in the clinical setting to predict 34 (2004); and Hinds, D. A. et al. Whole genome patterns of a response or non-response to an insulin sensitizer common DNA variation in human populations. Science 307, B. Association Studies with Both Genotype and Phenotype 1072-1079 (2005). A K means algorithm can be used to Data assign the measurements to clusters representing the three I0128 Both genotype and phenotype data may be used in distinct diploid genotypes that are possible: homozygous an association study in methods of the invention. Association reference, heterozygous, and homozygous-alternate. The studies using genetic variations as well as phenotypic varia K-means and background optimization steps are iterated until tions are described in U.S. patent application Ser. No. 11/043, cluster membership and background estimates converge. To 689, filed Jan. 24, 2005, entitled “Associations Using Geno determine the appropriate number of genotype clusters, the types and Phenotypes” which is incorporated herein by analysis can be repeated for 1, 2, and 3 clusters, and selecting reference. the most likely solution, considering likelihoods of the data I0129. Data on genetic variations from a plurality of indi and the cluster parameters. viduals with and without a phenotype-of-interest, i.e., respon siveness to an insulin sensitizer, is received, as described Quality Control above. It will be appreciated that the phenotype of interest, 0.125 Quality control filters can be applied to the data to e.g., response to an insulin sensitizer, is not the same as the assess the reliability of the fluorescence intensities of the phenotypes described in this section; these phenotypes are features for each SNP in an array scan. Applying these filters, used to determine the presence or absence between one or which are based on findings from numerous previous asso more of them and the phenotype of interest. ciation studies, increases the quality of the passing SNPs. 0.130. In the methods of the invention, the phenotype-of SNPs that pass the individual genotyping quality filters are interest is a response to an insulin sensitizer that would analyzed further. Such filters can be based on, e.g., combina include or exclude an individual from a drug trial or a drug tions of call rate and Hardy-Weinberg equilibrium p-values. therapy. See U.S. Provisional No. 60/566,302, filed Apr. 28, The specific combination chosen depends on the degree of 2004, entitled “Methods for Genetic Analysis”; U.S. Provi increase in quality of the passing SNPs desired. For example, sional No. 60/590,534, filed Jul. 22, 2004, entitled “Methods one filter requires a call-rate of 0.8, meaning that the SNP has for Genetic Analysis.” U.S. Ser. No. 10/956.224, filed Sep. an unambiguous genotype call in at least 80% of the samples: 30, 2004, entitled “Methods for Genetic Analysis,” and U.S. and a Hardy-Weinberg equilibrium p-value of >0.0001. SNP Ser. No. 11/510,261, filed Aug. 25, 2006, entitled “Methods call rates may be computed after discarding genotypes that for Genetic Analysis, all of which are incorporated herein by obtained<0.2 score with an individual genotyping error prob reference for all purposes. ability metric. In some embodiments, the metric uses I0131 Data on a group of phenotypes of the plurality of machine learning algorithm to approximate a probability of a individuals can also be received. The group of phenotypes genotype being discordant with outside platforms from 15 includes the phenotype-of-interest. Data on the group of phe QC and SNP-property based inputs. See, e.g., U.S. applica notypes can be received prior to, after, and/or concurrent with tion Ser. No. 10/970,761, filed Oct. 20, 2004, entitled “Analy the receipt the data of the genetic variations. In some embodi sis Methods and Apparatus for Individual Genotyping, and ments, data on the group of phenotypes is generated by a U.S. application Ser. No. 11/173,809, filed Jul. 1, 2005, practitioner of the present invention by, for example, obser US 2008/0280955 A1 Nov. 13, 2008 17

Vation (e.g., gross phenotypic trait), biochemical testing (e.g. opment/function), liver/hepatic system, locomotor activity, blood or urine analysis), or other diagnostic test (e.g., X-ray, lordosis, lung, lung development, lymph organ development, MRI, CAT scan, CT scan, Doppler shift, etc.). macrophages (e.g. antigen presentation), mammary glands, 0132) Examples of phenotype data that may be received/ maternal/paternal behavior, mating patterns, meiosis, mental collected include, but are not limited to, data about the indi acuity, mental stability, mental state, metabolism of Xenobi viduals: ability to roll the tongue, ability to taste PTC, acute otics, metaphysis, middle ear, middle earbone, morbidity and inflammation, adaptive immunity, addiction(s), adipose tis mortality, motor coordination/balance, motor learning, Sue, adrenal gland, age, aggression, amino acid level, amy mouth, movement, muscle, muscle contractility, muscle loidosis, anogenital distance, antigen presenting cells, audi degeneration, muscle development, muscle physiology, tory system, autonomic nervous system, avoidance learning, muscle regeneration, muscle spasms, muscle twitching, mus axial defects or lack thereof, B cell deficiency, B cells, B culature, myelination, myogenesis, nervous system, neuroc lymphocytes (e.g. antigen presentation), basophils, bladder ranium, neuroendocrine glands, neutrophils, NK cells, noci size/shape, blinking, blood chemistry, blood circulation, ception, nose, nutrients/absorption, object recognition blood glucose level, blood physiology, blood pressure, body memory, ocular reflex, odor preference, olfactory system, mass index, body weight, bone density, bone marrow forma oogenesis, operant or “target response', orbit, osteogenesis, tion/structure, bone strength, bone/skeletal physiology, osteogenesis/developmental, osteomyelitis, osteoporosis, breast size/shape, bursae, cancellous bone, cardiac arrest, outer ear, OXygen consumption, palate, pancreas, paralysis, cardiac muscle contractility, cardiac output, cardiac Stoke parathyroid glands, pelvis girdle, penile erection function, Volume, cardiomyopathy, cardiovascular system/disease, perinatal death, peripheral nervous system, phalanxes, phar carpal bone, catalepsy, cell abnormalities, cell death, cell ynx, photosensitivity, piloerection, pinna reflex, pituitary differentiation, cell morphology, cell number, cell-mediated gland, PNS glia, postnatal death, postnatal growth/weight/ immunity, central nervous system, central nervous system physiology, chemotactic factors, chondrodystrophy, chromo body size, posture, premature death, preneoplasia, propensity Somal instability, chronic inflammation, circadian rhythm, to cross the right arm over the left of vice versa, propensity to circulatory system, cleft chin, clonal anergy, clonal deletion, cross the right thumb over the left thumb when clasping hands T and B cell deficiencies, conditioned emotional response, or vise versa, pulmonary circulation, pupillary reflex, radius, congenital skeletal deformities, contextual conditioning, cor reflexes, reproductive condition, reproductive system, resis tical bone thickness, craniofacial bones, craniofacial defects, tance to fatty liver development, resistance to hyperlipidemia, crypts of Lieberkuhn, cued conditioning, cytokines, delayed respiration (e.g., rate, shallowness), respiratory distress or bone ossification, dendritic cells (e.g. antigen presentation), failure, respiratory mucosa, respiratory muscle, respiratory Di George syndrome, digestive function, digestive system, system, response to infection, response to injury, response to digit dysmorphology, dimples, discrimination learning, new environment (transfer arousal), ribs, salivary glands, drinking behavior, drug abuse, drug response, ear size/shape scoliosis, sebaceous glands, secondary bone resorption, Sei including ear lobe attachment, eating behavior, ejaculation Zures, self tolerance, senility, sensory capabilities, sensory function, embryogenesis, embryonic death, embryonic system physiology/response, sex, sex glands, shoulder, skin, growth/weight/body size, emotional affect, enzyme?coen skin color, skin texture/condition, skull, skull abnormalities, Zyme level, eosinophils, epilepsy, epiphysis, esophagus, sleep pattern, Social intelligence, Somatic nervous system, excretion physiology, extremities, eye blink conditioning, spatial learning, sperm count, sperm motility, spermatogen eye color/shape, eye physiology, eyebrows shape, eyelash esis, startle reflex, Sternum defect, stomach, Suture closure, length, face shape, facial cleft, femur, fertility/fecundity, Sweat glands, T cell deficiency, T cells (e.g., count), tarsus, fibula, finger length/shape, fluid regulation, fontanels, taste response, teeth, temperature regulation, temporal foregut, fragile skeleton, freckles, gall bladder, gametogen memory, tendons, thyroid glands, tibia, touch/nociception, esis, gastrointestinal hemorrhage, germ cells (e.g., morphol trachea, tremors, trunk curl, tumor incidence, tumorigenesis, ogy, depletion), gland dysmorphology, gland function, glu ulna, urinary system, urination pattern, urine chemistry, uro cagon level, glucose homeostasis, glucose tolerance, genital condition, urogenital system, Vasculature, vasoactive glycogen catabolism, granulocytes, granulocytes (e.g., bac mediators, vertebrae, vesicoureteral reflux, vibrissae, vibris tericidal activity, chemotaxis), grip strength, grooming Sae reflex, viscerocranium, visual system, weakness, widows behavior, hair color, hair follicle structure? orientation, hair peak or lack thereof, etc. See, e.g.: U.S. patent application growth, hair on mid joints, hair texture, handedness, hard Ser. No. 11/043,689, filed Jan. 24, 2005, entitled “Associa erian glands, head, hearing function, heart, heart rate, heart tions. Using Genotypes and Phenotypes, the disclosure of beat (e.g. rate, irregularity), height, hemarthrosis, hemolym which is incorporated herein in its entirety. phoid system, hepatic system, hitchhiker's thumb, 0.133 Additional examples of phenotype data that may be homeostasis, humerus, humoral immune response, hypoplas received/collected about individuals can include phenotype tic axial skeleton, hypothalamus, immune cell, immune sys data about previous medical conditions or medical history tem (e.g., hypersensitivity), immune system response/func (e.g., whether an individual has had Surgery, experienced a tion, immune tolerance, immunodeficiency, inability to particular illness, given vaginal or nonvaginal childbirth, urinate, increased sensitivity to gamma-irradiation, inflam been diagnosed with mental illness, has allergies, etc.). matory mediators, inflammatory response, innate immunity, I0134. In some embodiments, phenotype data may also be inner ear, innervation, insulin level, insulin resistance, intes received/collected on the individuals family history. For tinal bleeding, intestine, ion homeostasis, jaw, kidney hem example, data can be collected on relatives Suffering from or orrhage, kidney Stones, kidney/renal system, kyphoscoliosis, affected by baldness, cancer, diabetes, hypertension, mental kyphosis, lacrimal glands, larynx, learning/memory, leuko illness, mental retardation, attention deficit, infertility, erec cyte, ligaments, limb dysmorphology, limb grasping, lipid tile dysfunction, cardiovascular disease, allergies, drug chemistry, lipid homeostasis, lips size/shape, liver (e.g. devel addiction, etc. US 2008/0280955 A1 Nov. 13, 2008 18

0135 Data on one or more phenotypes is received for sis, regression and correlation analysis, and multivariant dis individuals with a phenotype-of-interest and without the phe criminant analysis (see U.S. Pat. No. 4,791.998, which is notype-of-interest (i.e., responsiveness to an insulin sensi incorporated herein by reference for all purposes). tizer). In some embodiments, a larger set of possible pheno 0.139. The genetic variations and the data on the group of types is used in the association study to provide the greatest phenotypes are used collectively in association studies with probability of identifying the phenotype-of-interest in an one (or more) phenotypes-of-interest. Alternatively, or in individual who may or may not be in case or control groups. For example, data on more than 2, more than 3, more than 5, addition, the correlation may be conducted through pooling more than 7, more than 10, more than 15, more than 20, more samples to reduce overall costs or by genotyping individual than 25, more than 30, more than 35, more than 40, more than samples, as described for genotyping studies. 45, more than 50, more than 60, more than 70, more than 80, 0140. One or more phenotypes from the group of pheno more than 90, or more than 100 phenotypes may be used in an types are identified that can differentiate at least in part among association study. individuals having and not having responsiveness to an insu 0.136 Data on the group of phenotypes may be received in lin sensitizer. This can be achieved by identifying phenotypes a binary system (e.g., 0’s and 1s) or a greater-fold system from the group of phenotypes with significant frequency dif (e.g., three-fold, four-fold, etc., Such as 0's, 1's 2's, etc.) on a ferences between cases and controls. In certain embodiments, phenotype-by-phenotype basis. An example of phenotypic steps the identification of phenotypes and genotypes that can data that may be received in a binary system includes the differentiate at least in part among individuals having and not presence (or absence) of a disease. If an individual has a having responsiveness to an insulin sensitizer occur simulta particular phenotype (e.g., disease) from a group of pheno neously. types, that phenotype may be designated as '1'. Conversely, 0.141. In some embodiments, it is predicted whether an if an individual does not have a particular phenotype from a individual (that can be from neither the case nor the control group of phenotypes, that phenotype may be designated as groups) has or does not have responsiveness to an insulin “O. sensitizer. This step optional. Further, a treatment. Such as a 0.137 Similarly, data on the group of phenotypes may also drug treatment is administered (or not administered) to a be received in a greater-fold system, Such as a three-fold, patient, or a patient is enrolled in a clinical trial, based on the four-fold system, or a greater-fold system (e.g., more than results of the predictive step. 10-fold, more than 20-fold, or more than 40-fold). In greater 0.142 Table 2 below illustrates hypothetical data received fold systems each of the multiple forms of a phenotype may from six individuals. The data includes information on four be designated with a different number. For example, if an genetic variations (common SNPs) and four phenotypes. For individual expresses a first form (e.g., blue eyes) of a pheno SNPs, the following letter symbols are used: (A) adenine (T) type (e.g., eye color) of a group of phenotypes, that phenotype thymine (C) cytosine, and (G) guanine to indicate SNP alle may be designated as '1', a second form (e.g., green eyes) of les.

TABLE 2 Association Study. Using Common SNPs (CSS) and Phenotypes (Phs Phenotype-of interest (responsiveness to an insulin Individual sensitizer) SNP 1 SNP 2 SNP 3 SNP 4 Phenotype 1 Phenotype 2 Phenotype 3 Phenotype 4 G T l O 2 7 G T l O 1 8. C A. O 1 O 1 C A. O 1 2 2 G T l O 2 9 C A. O 1 O 1 the phenotype of a group of phenotypes may be designated as 0143. As illustrated by Table 2, individuals 1, 2, and 5 have “2, a third form (e.g., brown eyes) of the phenotype of a responsiveness to an insulin sensitizer (symbolized by a “1”) group of phenotypes may be designated as '3', etc. are cases, while individuals 3, 4, and 6 do not have respon 0.138. Data on the plurality of phenotypes about an indi siveness to an insulin sensitizer (symbolized by a “0”) are vidual can also include data about a degree to which Such controls. The presence of “A” allele at SNP1, a “G” allele at phenotypes or plurality of phenotypes is present (or absent) in SNP3, and/or a “T” allele at SNP4 are associated with an the individual. For example, the degree of skin pigmentation individual having responsiveness to an insulin sensitizer can be expressed as a gradient from 1 to 10 wherein “1” (“1”); while the presence of an “T” allele at SNP 1, “Callele represents the lightest skin color and “10' represents the at SNP3, and/or an 'A' allele at SNP4 is associated with an darkest skin color. Determination of the degree of skin pig individual not having responsiveness to an insulin sensitizer mentation can be made by an observer (e.g., clinician) or can (“O). be made based on a plurality of other determinants using 0144. Similarly, a phenotype score of “1” for phenotype 1, various mathematical-statistical methods including, but not a phenotype score of “0” for phenotype 2, and/or a phenotype limited to, multiple comparison (Bonferroni), variance analy score of “7 or higher for phenotype 4 is associated with an US 2008/0280955 A1 Nov. 13, 2008

individual having responsiveness to an insulin sensitizer 0149. In a related embodiment, SNPs associated with the (“1); while a phenotype score of “0” for phenotype 1 a efficacy of a drug, e.g., an insulin sensitizer drug may be used phenotype score of “1” score for phenotype 2, and/or a phe to improve the efficacy of the drug by Stratifying patient notype score of "2 or less” is associated with an individual not populations to exclude probable nonresponders from treat having responsiveness to an insulin sensitizer (“0”). ment. In one example, ~32% of patients exposed to an insulin sensitizer drug are classified as responders. An association 0145 Combining these data into a single association study is performed with a case group of responders and a study, one can predict that an individual with an 'A' allele at control group of nonresponders, and 25 SNPs are found to be SNP1, “G” allele at SNP3, and/or “T” at SNP4, having a associated with the responder phenotype. Based on the scores phenotype score of “1” for phenotype 1, phenotype score “0” calculated for the cases and controls it is found that 81% of for phenotypes 2, and/or phenotype score of “7 or higher for responders and 40% of nonresponders have a score of >19. phenotype 4, will have responsiveness to an insulin sensitizer Therefore, using 19 as a threshold value to stratify a patient (“1”). Conversely, an individual with a “T” allele at SNP1, a population prior to administering the insulin sensitizer drug “C” allele SNP3, and/or an “A” allele at SNP4, having a improves the overall efficacy of the drug from ~32% to ~50%. phenotype score of “0” for phenotype 1, phenotype score of In doing so, the number of nonresponders exposed to the “1” for phenotype 2, and/or phenotype score of “2 or less' for insulin sensitizer drug is decreased Substantially, and those phenotype 4 will not have responsiveness to an insulin sen excluded may then be treated with alternative therapies sitizer (“0”). Sooner. A change in efficacy of this magnitude could help to 0146 Data analysis and use FIG. 1 is a high-level block get a new drug approved, or could encourage wider use of an diagram of a computer system 100 for storing and processing already approved drug. data from one or more individuals 102. The data can include genetic data (e.g., genetic variations) and, optionally, pheno C. Association Studies and Methods for Classes of Drugs. type data. For screening uses, one or more genetic variations 0150. The invention also includes methods and composi and/or phenotypes may be input. For association studies, the tions for Screening individuals for one or more genetic varia data may further include data regarding response to one or tions (e.g., SNPs) and/or one or more phenotypic variations more insulin sensitizers. The data are entered into the system that predicts responsiveness to a first drug, and using this via an input device 104. Illustrated are at least one processor association to determine whether or not to modulate the treat 106 coupled to a bus 122. Also coupled to the bus 122 are a ment of an individual with a second drug, where the first and memory 108, a storage device 110, an input device 104, a Second drugs belong to the same class of drugs. In Some graphics adapter 114, and a network adapter 118. A display embodiments, the class of drugs is insulin sensitizers. In some 116 may be coupled to the graphics adapter 114. A secondary embodiments, the first and second drugs are the same drug. In information processing and/or display system 120 is illus Some of these embodiments, the second drug is netoglitaZone trated, which may be, e.g., a computer or other device that has and the first drug is an insulin sensitizer for which clinical or access to a network, e.g., the Internet. Not all components other data is available as well as either association studies described must be present for the use of methods and com with genotypes, or materials with which to perform Such positions of the invention. studies. Drugs for which clinical data is available that are 0147 The at least one processor 104 may be any general insulin sensitizers include troglitaZone, rosiglitaZone, piogli purpose microprocessor. The storage device 110 may be any taZone, muraglitazar, galidatesaglitazar, 677954, MBX-102, device capable of holding data, like a hard drive, compact disk T131, LY818, LY929, and PLX204. Using these methods and read-only memory (CD-ROM), DVD, or a solid-state compositions, the use of the second drug may be refined and memory device. The memory 108 holds instructions and data targeted, so that, e.g., clinical trials for the second drug are used by the processor 106. The input device 104 may be, e.g., more likely to be performed on patient populations likely to amouse, track ball, lightpen, touch-sensitive display, or other benefit from the drug and/or unlikely to suffer adverse effects. type of pointing device, that is used in combination with a The methods and compositions of the invention thus allow keyboard to input data into the computer system. Data may much more targeted and precise testing and clinical use of also be input directly from devices or instruments that are drugs in a class of drugs. used to assay genetic, phenotypic, and/or insulin sensitizer 0151. A “class of drugs.” as used herein, includes a group response data from the individual 102. The graphics adapter of two or more drugs that are placed in the group through 114 displays images and other information on the display Some common characteristic or characteristics. A “character 116. The network adapter 118 couples the computer system istic' is any trait that may be repeatably associated with a drug 100 to a local or wide area network. or a composition containing the drug, Such as, but not limited 0148. In some embodiments, data from one or more indi to, structure, mechanisms, stereochemistry, crystal form, for viduals are input into the computer system in one location, mulation, dosage, dosage route, dosage frequency and/or and further analyzed, displayed, or otherwise manipulated at duration, effects in an animal model, empirically-found traits, a remote location. For example, some or all of the data of an use in combination with other therapies or drugs, combina association study may be acquired in one country and trans tions thereof, and the like. The characteristic(s) may be asso ferred to another country for analysis. Another example is that ciated with significant predictability of an effect of the drugs, data from an individual to be screened may be acquired at a i.e., drugs placed in the same class because they share a laboratory, e.g., a reference laboratory Such as a Clinical common characteristic have a greater than random chance of Laboratory Improvement Amendments (CLIA) laboratory, having the same or similar therapeutic or non-therapeutic and transferred to another location, e.g., a doctor's office, effect. A drug may be in more than one class, depending on where it is further processed and/or displayed. The data may the characteristic(s) used as criteria for the classes. be moved to the remote location by any means, e.g., as data on 0152 Rather than focusing on a single drug, the methods a CD-ROM, or via a network, e.g., the Internet. provide information on the likelihood that an individual will US 2008/0280955 A1 Nov. 13, 2008 20 be a responder or non-responder for a series of related drugs, clinical trials for drug B may be treated by alternative drugs or and, if a responder, whether the response will be a therapeutic methods; in Some cases the alternative drug and/or treatment or a non-therapeutic effect, e.g. an adverse effect. Thus, in may also be based at least in part on the results of the asso Some embodiments, an association study is performed to ciation studies of drug A (e.g., the individual may be treated identify one or more genetic variations, e.g., SNPs and/or with a drug of a different class than drug A and drug B). In phenotypes, associated with one or more responses to a first Some embodiments in which the drug in clinical trials is not drug in a class of drugs, and those variations are used to administered to certain individuals, those individuals can be modulate the administration of a second drug in the class of placed in a different clinical trial of another therapeutic agent drugs. The administration of the second drug may be in a acting through a different mechanism than the drug for which research setting (e.g., a clinical trial), in a clinical setting (e.g., the individual was screened. use of the drug in treatment of a disease), or in any other 0156. In some embodiments, the results of the association setting in which it is useful to predict the effect of the second studies for drug Aare used to modulate a clinical trial for drug drug (e.g., in commercialization of the second drug). "Modu B by altering the administration of drug B. For example, lation of administration includes not administering the sec various aspects of treatment with drug B may be modulated ond drug, administering the second drug in a manner similar based on association studies of drug A. For example, modu to the first drug (e.g., dosage, dosing schedule, duration of lating administration may include: adjusting the dosage of the treatment, and the like), or altering the administration of the drug, route of administration of the drug, duration of treat second drug in comparison to administration of the first drug. ment with the drug, or frequency of administration of the Modulation of administration is discussed in more detail else drug; changing the type of carrier of the drug, enantiomeric where herein. form of the drug, crystal form of the drug, tautomeric form of 0153. Screening of an individual for genetic variations the drug; administering a fragment, analog, and/or variant of associated with a response to a first drug in a class of drugs is the drug; or a combination thereof. Thus, for example, the useful, for example, to identify individuals who may be dose size and/or frequency may be adjusted for drug B based enrolled in (or excluded from) a clinical trial of a second drug on predictions from association studies of drug A as to an in the class of drugs, and/or individuals who may suffer (or individual's degree of therapeutic and/or non-therapeutic not suffer) an adverse reaction from a second drug in the class responsiveness to drug B. For example, those predicted to be of drugs. For example, in Some embodiments, results of an mild responders but who are also predicted to have few or no association study with a first drug in a class of drugs are used adverse effects could be given a larger relative dose than those to screen individuals in patient populations for clinical trials predicted to be normal or superresponders. Another example of second drug in the class, in order to exclude individuals is in, e.g., cancer chemotherapy trials, where the dosage of the predicted to have adverse response to the second drug, and/or chemotherapeutic agent is often adjusted based on the indi to include individuals predicted to have a desired response or vidual's therapeutic response coupled with the individual’s degree of response to the second drug, and/or to otherwise adverse effects. Thus, an individual who is predicted from modulate the administration of the second drug. genotype data, based on association data from a chemothera 0154 An exemplary embodiment is illustrated in FIG. 2. peutic drug in a given class, to be a mild responder with large During, e.g., a clinical trial or routine clinical use of drug A adverse effects to another drug in the class for which associa that is member of class of drugs (in this example, drugs that tion studies are not available, may receive a lower dose, or no act through mechanism X are placed in the same class), dose, of the drug, compared to an individual predicted to be a samples may be taken from individuals that are genotyped at superresponder with few adverse effects, who would receive sets or Subsets of polymorphic loci, e.g., SNPs, and associa a high dose of the drug. tion studies may be performed to determine the relationship 0157. The association studies with drug A are used to between responses of individuals to drug A and genotypes of predict the response of an individual to drug B, e.g., in a the set or subsets of SNPS, as described herein. Responses clinical trial or in the course of clinical treatment. For any may include therapeutic responses, including degrees of given genotype (e.g., at one or more SNPs) and/or phenotype, responsiveness (e.g., minimal responders vs. average a predictive probability of a response to drug A may be responders vs. 'Superresponders'). Responses may also established from association studies of drug A. Decisions include non-therapeutic responses, e.g. side effects such as regarding modulation of the administration of drug B based adverse effects. When another drug B, which also acts or is on the genotype and/or phenotype of an individual can be thought to act through mechanism X, is subjected to clinical made based on a pre-determined level of predictability for a trials, the results of the association studies for drug A may be response (desired, undesired, or a combination thereof) in used to modulate, e.g. the design of the clinical study, the that individual to drug A. In some embodiments, the degree of enrollment in the clinical study, stratification of individuals probability that a response or combination of responses to enrolled in the study, and/or prediction of or analysis of drug A will occur that is used as a cutoff for decision as to the results of the clinical trial of drug B. Of course, association use of drug B (e.g., inclusion or exclusion in a clinical trial) is studies may also identify phenotypic traits that are associated greater than about 99.9, 99.5, 99,98, 97,96.95,94.93, 92,91, with the drug response, e.g., as described in U.S. Ser. No. 90, 85,80, 75, 70, 65, 60,55, 50, 45,40,35, 30, 25, 20, 15, 10, 11/043.689, filed Jan. 24, 2005, entitled “Associations. Using 5, 4, 3, 2, 1, 0.5, or 0.1%. In some embodiments, the degree of Genotypes and Phenotypes.” probability that a response or combination of responses to O155 In some embodiments, the results of the association drug A will occur that is used as a cutoff for decision as to the studies for drug A are used to include or exclude individuals use of drug B (e.g., inclusion or exclusion in a clinical trial) is from the clinical trials for drug B. Typically, individuals are less than about 99.9, 99.5, 99,98, 97,96, 95, 94, 93, 92,91, Subject to exclusion if their genotype and/or phenotype indi 90, 85,80, 75, 70, 65, 60,55, 50, 45,40,35, 30, 25, 20, 15, 10, cates susceptibility to adverse effects or lack of responsive 5, 4, 3, 2, 1, 0.5, or 0.1%. The use of more than one genotype ness, or a combination thereof. Individuals excluded from and/or phenotype can increase the predictiveness for drug A US 2008/0280955 A1 Nov. 13, 2008

used as a cutoff for drug B. For example, the use of genotype done in combination with inclusion or exclusion in the clini at more than one genetic variation, e.g., SNP can increase the cal trial of drug B based on association studies using drug A. degree of predictiveness as to a given response to a drug. In Predictions to be tested may include non-therapeutic effects, some embodiments about 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, Such as adverse effects, or lack thereof (e.g., if those thought 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 500, 1000, to be susceptible to adverse effects are excluded from the 10,000, 100,000, 1,000,000, or more than about 1,000,000 trial). Predictions to be tested may also include degree of genetic variations, e.g., SNPs, are used to reach the desired response, e.g., mild response, normal response, or Superre level of probability for outcome with drug A used as a cutoff Sponse. for deciding whether or not to modulate use of drug B. 0.161. In addition to predicting responses for new drugs in 0158. In some embodiments, the response to the drug is an a class, drugs that were withdrawn from the market or from adverse effect, and a probability cutoff is used to limit the clinical trials for adverse effects (e.g., troglitaZone, various patient population administered a second drug in the same COX-2 inhibitors) or because average efficacy was poor (e.g., class. It will be appreciated that the probability cutoff can be villazodone and eptrapirone for depression) may be “rehabili lower or higher depending on the severity of the adverse tated when genetic profiles and association with efficacy effect, in combination with the type of patient population to and/or adverse effects are known for one or more other drugs be treated. For example, in a cancer chemotherapeutic trial in in the same class. Thus, for example, troglitaZone can be which a fatal adverse effect may occur, but where the patient retested when genetic profiles for other PPAR agonists and population is composed of terminal patients, a higher prob their associated adverse effects are known. A further example ability cutoff would be tolerated than in a study of an antiin is the retesting of VilaZodone and eptrapirone when efficacy flammatory drug to reduce pain and inflammation with the associations with genetic profiles for other serotonin agonists same fatal adverse effect, but studied in a patient population become available. Patient populations can be pre-screened composed of individuals suffering from mild to moderate and those with genetic profiles associated with a pre-deter inflammation. Thus, in the former case, a probability for the mined probability of adverse effects can be excluded the trial, fatal adverse effect based on genotype association studies of and/or those with genetic profiles associated with a predeter a known drug in the class may be set at less than about 50, 45. mined probability of increased efficacy may be selected for 40, 35, 30, 25, 20, 15, 10, or 5%. In the latter case (e.g., for the trial. In this way, drugs that would otherwise not be COX-2 inhibitors and other drugs where the adverse effects available to patients due to their failure in clinical trials or were of sufficient severity that the drug was withdrawn from their withdrawal from the market, but that are effective (pos the market) allow probability, e.g., less than about 10, 5, 1,0.5, sibly highly effective) in a subgroup of patients, may become 0.1, 0.05, 0.01, 0.005, or 0.001% may be used. Thus, in some available and benefit select patient populations. embodiments, the probability that a fatal or life-threatening 0162 The invention also provides a drug that is approved adverse effect would occur for a given genotype for drug A is for use by a regulatory agency, where the drug is a member of used in deciding whether to administer a drug B in the same a class of drugs, and where the drug is tested for approval by class as A to an individual (e.g., in a clinical trial), based on the regulatory agency in a method that comprises screening the genotype of an individual. an individual for one or more genetic variations and/or phe 0159. In other embodiments it may be desired merely to notypes associated with response to another drug in the class increase the probability that a sufficient number of responders of drugs, and modulating or not modulating the administra to a new drug be included in a clinical trial to provide signifi tion of the drug based on the results of said testing. In some cant results. This can be the case where a drug A in a class of embodiments, the decision to modulate or not modulate the drugs was found to cause a therapeutic response in only a administration of the drug to be tested, and/or the modulation certain percentage of people, and the percentage was not high which is chosen, is based on a predetermined probability of enough to justify its use and/or approval. If drug B in the same response to the drug that has already been tested, based on the class of drugs is to be tested, it is desired to increase the one or more genetic variations in the individual. In some number of responders to a sufficient level to indicate the embodiments the drug to be tested is a drug that has not efficacy of drug B for use. In such cases, the cutoff probability previously been tested for approval by the regulatory agency. for modulation of administration of drug B to an individual In some embodiments, the drug to be tested is a drug that was (e.g., inclusion or exclusion in a clinical trial) may be greater previously tested but not approved for use, or approved for than about 50, 60, 70, 80, 90, 95, 98.99%. An example of a use but withdrawn from the market. In some embodiments, drug that would benefit from such a prediction is the use of the regulatory agency is the Food and Drug Administration altered peptide ligands (APLs) in the treatment of multiple (FDA). In some embodiments, the testing is a Phase I, Phase sclerosis. It appears that APLs are only effective in small II, Phase III, or Phase IV clinical trial. In some embodiments, Subgroups of patients. The methods and compositions of the the drug is an insulin sensitizer, e.g., netoglitaZone. In some invention allow researchers and clinicians to increase the embodiments, the drug is a drug that was withdrawn from use: degree of certainty in designing clinical trials for emerging in Some embodiments the drug is selected from the group APLS, as well as in selecting patients for administration of an consisting of azarabine, troglitaZone, fenfluramine, dexfen APL, thus increasing the value and usefulness of these drugs. fluramine, terfenadine, mibefradil, astemizole, cisapride, Without such increased certainty, researchers are less likely to alosetron, grepafloxacin, bromfenac, rapacuronium bromide, persist in investigation, and clinicians are less likely to pre Valdecoxib, rofecoxib, thalidomide, diethylstilbersterol, tic scribe the drugs, given the inability to predict their effective rynafen, methaquinone, traZolam, cerivastatin, fluoroxamine CSS. maleate, natalizumab, and hydromorphone HCl extended 0160. It will be appreciated that various combinations of release. Further drugs withdrawn from use in the U.S. include responses, as well as desired results, can resultina probability adenosine phosphate, azaribine, benoxaprofen, bithionol, cutoff for modulation of administration of drug B that may be parenteral butamben, oral gel drug products containing car any desired probability for response to drug A. This can be betapentane citrate, chlorhexidine gluconate for use on skin, US 2008/0280955 A1 Nov. 13, 2008 22 chlormadinone acetate, chloroform, diamthazole dihydro 0.165. In some embodiments the database is recorded in a chloride, dibromsalan, dihydrostreptomycin Sulfate, dipy tangible medium, Such as a computer data storage medium, rone, encainide hydrochloride, flosequinan, mepazine hydro e.g., hard drive, compact disc, or the like. In some embodi chloride or mepazine acetate, metabromsalan, parenteral ments the invention encompasses the transmission of data methamphetamine hydrochloride, methapyrilene, methopho contained in a database as described herein from one location line, nitrofuraZone, nomifensine maleate, oxyphenisatin, to another by, e.g., electronic means such as transmission via oxyphenisatin acetate, phenacetin, phenformin hydrochlo the Internet. ride, pipamazine, potassium arsenite, povidone, reserpine 0166 It will be appreciated that as data is accumulated for (more than 1 mg in oral dosage), Sparteine Sulfate, Sul members of a class of drugs or classes of drugs, the predictive fadimethoxine, Sulfathiazole, Suprofen, temafloxacin hydro power of associations will become greater, and that further chloride, 3,3',4',5-tetrachlorosalicylanilide, tetracycline for refinements in the classification of the drugs can become pediatric use at greater than 25 mg/ml, tribromsalan, trichlo apparent. roethane, and Zomepirac sodium. Drugs withdrawn from use 0.167 As one example, a subgroup of drugs within a par in European Union include Valdecoxib, parecoxib, sildenalfil. ticular class of drugs may exhibit the same or similar asso rosiglitaZone, apomorphine hydrocloride, desloratadine, ciation profiles between response to the drugs and one or dofetilede. Votumamab, olanzapine, fomivirsen, imiquimod, more genetic variations, e.g., SNPs and/or phenotypes, and ganiciclovir, rotavirus vaccine, combined diptheria, tetanus, these association profiles may differ from other members of and acellular pertussis vaccine, dodecafluoropentane, and the class. In some embodiments a new classification may be formed for these drugs based on a characteristic common to levacetylmethadol. The methods may also be applied to drugs this subgroup but absent in some, most or all of the other that have not been withdrawn or failed clinical trials, but that members of the class. This characteristic may then be used in have warnings concerning their use. The methods may also be future association studies for drugs in this class to further applied to drugs for which no withdrawal or warning is pres Subclassify them into the new Subgroup in order to increase ently in effect. the predictive power of genotypes and/or phenotypes of indi 0163 The methods may also be used in the treatment of viduals for responsiveness to new drugs in this subgroup. In individuals. In some embodiments, an individual Suffering Some embodiments, the characteristic common to the drugs in from a disorder may be screened for a genetic variation and/or this new Subgroup but absent in Some, most, or all of the other phenotype that indicates responsiveness to a class of drugs members of the class may also be investigated in drugs in used to treat that disorder. In some embodiments, a study to other classes of drugs to determine if it correlates with greater determine the association between one or more genetic varia degrees of predictability of a particular response in these tions and responsiveness to a first drug in a class of drugs may other drugs. In some embodiments, the new common charac be used to determine a treatment of an individual with a teristic will be used to model a new mechanism common to second drug in the class of drugs, or may be used to determine the drugs with this characteristic that explains some or all of that the individual should be treated with a drug in a different the drug responses associated with this characteristic. In some class of drugs. Typically, the second drug will be a drug for embodiments the new common characteristic will be used to which association studies have not been performed, or have design new drugs that cause the response associated with the not been performed to the same extent as for the first drug. In characteristic in individuals with the genotype and/or pheno some embodiments, the disorder is a disorder of blood glu type associated with this response. For example, it may be cose regulation, e.g., an insulin resistance disorder, as found that drugs with characteristic X are found to have a described herein. In some embodiments, the class of drugs is response of longer half-life in individuals with genotype A. PPAR modulator insulin sensitizers. New drugs may be designed with characteristic X in the 0164. The invention further encompasses a database con expectation that they will have alonger half-life in individuals taining data regarding one or more drugs, and associations with genotype A. between one or more genetic variations and/or phenotypic 0.168. As another example, in some embodiments a drug variations, one or more responses of individuals to the drug or that has not been tested for association between genotype drugs, and one or more characteristics of the drugs. The and/or phenotype and response to the drug is assigned a database may contain data for at least about 1, 2, 3, 4, 5, 6, 7, “closest relative' in the database of drugs, based on one or, 8, 9, 10, 11, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, 50, 60, typically, more than one characteristic of the untested drug. 70, 80,90, 100, 150,200, 500, 1000, or more than 1000 drugs. The closest relative is the drug that most closely matches the The drugs may be in a single class of drugs, or in more than untested drug in the characteristic(s). The characteristic(s) one class of drugs. In some embodiments, all or Substantially may be any characteristic(s) associated with the new drug and all drugs in a class for which data are available are included the closest relative. The closest relative is used to provide the database. Alternatively, the database may contain infor predictive association data for responses of individuals to the mation concerning drugs in at least about 2, 3, 4, 5, 6, 7, 8, 9. new drug based on the genotypes and/or phenotypes of the 10, or more than 10 classes of drugs. In some embodiments, individuals. The actual responses of individuals to the new the database contains association data for all or Substantially drug and their genotypes and/or phenotypes can then be all drugs for which data are available. The database can be monitored and used to refine the criteria for picking the clos updatable, and updates can be available for those using the est relative. For example, data for the new drug can be com database, e.g., through the internet. Such a database allows pared with predicted responses for some or all of the other empirical associations to be made between drugs in different drugs in the database that share one or more characteristics mechanistic or structural classes which nonetheless have with the new drug, and with predicted responses for its closest similar genetic variation profiles for their therapeutic effects. relative, to determine whether the chosen closest relative was, In some embodiments one or more of the genetic variations indeed, the drug with the highest predictive powerfor the new are SNPS. drug. If not, the algorithm for choosing a closest relative is US 2008/0280955 A1 Nov. 13, 2008

revised to reflect the difference, e.g., the criteria what consti types and/or phenotypes that have been found for old drug B tutes a “match' between characteristics of an untested drug to predict a high degree of efficacy, less severe or low rate of and drugs in the database can be changed based on the new adverse effects, or other desirable effects. Such marketing data. In this and similar ways, as data accumulates in the may be directed to health care professionals and/or to database, characteristics used to group drugs into classes can patients. be refined and altered in order to increase the predictive power 0172. In some embodiments the invention further provides of the classifications, to model new mechanisms of drug an isolated nucleic acid that specifically hybridizes to a action, to design new drugs, and the like. genomic sequence within a region containing a nucleic acid 0169. The invention further provides software to deter associated with a response to a first drug in a class of drugs, mine whether a drug has a characteristic or characteristics; to for use in diagnostics, prognostics, prevention, treatment, or determine a drug's closest relative and/or class or classes study of a response to a second drug in the class of drugs. In given the characteristic or characteristics; to predict the prob some embodiments the region extends from about 10 kb ability that a given response will occur for a drug (e.g., an upstream to about 10 kb downstream of the nucleic acid. In untested drug's closest relative, or a member of the class of some embodiments the region extends from about 5 kb drugs in which the untested drug has been placed) in the upstream to about 5 kb downstream of the nucleic acid. In database given the presence of a genotype and/or phenotype; some embodiments the region extends from about 2 kb to Suggest best modulations for administration of an untested upstream to about 2 kb downstream of the nucleic acid. In drug based on a genotype of an individual; algorithms for some embodiments the region extends from about 1 kb refining the database and for refining other algorithms in the upstream to about 1 kb downstream of the nucleic acid. In Software based on new data for new drugs, genotypes, phe Some embodiments the invention provides an isolated nucleic notypes, or responses; and the like. acid that specifically hybridizes to the nucleic acid sequence 0170 In one aspect, the invention provides kits. The kits itself. In some embodiments, a set of nucleic acids is pro contain a testing component for testing one or more genetic vided, where the nucleic acids of the set are related (e.g., are variations in an individual in order to genotype the individual complementary) to some or all of the genetic variations asso for the one or more variations, contained in packaging. In ciated with a response to a first drug in a class of drugs, foruse Some embodiments, the testing component comprises one or with a second drug in said class of drugs, in diagnostics, more nucleic acids, as described herein. In some embodi prognostics, prevention, treatment, or study of a response to ments, the genetic variations are SNPs. In some embodi the second drug. In some embodiments, the class of drugs is ments, the testing component is a microarray, e.g., a SNP insulin sensitizers, e.g., PPAR modulator insulin sensitizers chip. In some embodiments, the kits further include a data such as thiazolidinedione PPAR modulators. In some base or access to a database for one or more drugs and the embodiments, the nucleic acid is immobilized on a solid associations between genetic variations and/or phenotypic Support. In some embodiments, a set of nucleic acids immo variations that may be tested with the testing component or bilized on a solid support is provided, where the nucleic acids that may be otherwise observed, and responses to the one or of the set are related (e.g., are complementary) to some or all more drugs. The kits may further include Software or access to of the genetic variations, e.g., SNPs, associated with a Software to determine whether a drug has a characteristic or response to a drug in a class of drugs. characteristics; to determine a drug's closest relative and/or 0173 The identification of genetic variations in the indi class or classes given the characteristic or characteristics; to vidual may be done by any Suitable means, as described predict the probability that a given response will occur for a herein. See e.g., U.S. Pat. No. 6,897.025; and U.S. patent drug (e.g., an untested drug's closest relative, or a member of application Ser. Nos. 10/448,773 entitled “Methods for the class of drugs in which the untested drug has been placed) Genomic Analysis, filed May 29, 2003: 10/042,819, entitled in the database given the presence of a genotype and/or phe “Genetic Analysis Systems and Methods.” filed Aug. 21, notype; to Suggest best modulations for administration of an 2003: 10/786,475 entitled “Analysis Methods for Individual untested drug based on a genotype of an individual; algo Genotyping, filed Oct. 21, 2004; and 10/845,316 entitled rithms for refining the database and for refining other algo “Allele-Specific Expression Patterns.” filed Jan. 6, 2003. Suit rithms in the Software based on new data for new drugs, able means also include gel-based genotyping, nanofluidics, genotypes, phenotypes, or responses; and the like. The kit hybridization to nucleic acid probe arrays, and single base may further contain instructions for use of the components of addition sequencing (see, e.g., U.S. Pat. No. 6,911.345). the kit, as well as other components useful in Sampling for and using the means for genetic testing, components useful in 1. Classes of Drugs sample preparation such as components for amplifying 0.174 Drugs may be classed into mechanistic classes, nucleic acids (e.g., PCR components), gloves, eye protection, structural classes, classes based on pharmacological effect, cleaning Substances, buffers, primers, enzymes, labels, and and other classes of drugs that are based on the chemical or the like. biological nature of the drugs, or that are empirically based. 0171 In one aspect, the methods of the invention include (0175 Mechanistic classifications are based on the mecha business methods. In one embodiment, the invention provides nism of action of drugs, e.g., receptor targets or other targets a method comprising using the results of an association study of the drugs. For example, drugs that primarily act on the that predicts the association between one or more genetic autonomic nervous system may be classed as cholinorecep variations (and/or phenotypes) and responsiveness to a first tor-activating drugs, or cholinesterase-inhibiting drugs, or drug to market a second drug, where the first and the second cholinoceptor-blocking drugs, or adrenoceptor-activating drugs are members of the same class of drugs. For example, drugs, or adrenoceptor-blocking drugs. new drug A may belong to the same class of drugs as old drug 0176) However, as is known in the art, often drugs do not B, for which association data are available. New drug A may have a known target or a precisely defined mechanism, and be marketed for use with those individuals exhibiting geno may be classed according to similarities in other aspects the US 2008/0280955 A1 Nov. 13, 2008 24 drugs, such as similarities of the chemical structure that are cutaneous, ocular, inhalation, oral. Sublingual, Suppository, thought to be important to the action of the drugs. Such skin, via pump, and the like), formulation type (e.g., rapid similarities include structural components, optical isomer acting, Sustained release, enterically coated, etc.), mode of ism, crystal structure, and the like. uptake and delivery to site of action, metabolism (e.g., drugs 0177. Drugs may also be classed based on their major metabolized through Phase I reactions such as oxidation via pharmacological action, e.g., lipid-lowering drugs, antide hepatic microsomal P450 system and subclasses thereof, through oxidation via nonmicrosomal mechanisms and Sub pressants, anxiolytics, and the like. The second drug may be classes thereof, through reduction, through hydrolysis and placed in the same class as the first drug by in vitro and/or in subclasses thereof; drugs metabolized through Phase II reac Vivo studies; in some embodiments, action through the same tions such as glucoronidation, acetylation, mercapturic acid or similar mechanism may be predicted from structural analy formation, Sulfate conjugation, N-, O-, and S-methylation, S1S trans-Sulfuration; and combinations thereof), metabolic prod 0178. In some embodiments, drugs are classified based on ucts and/or byproducts and their structure and/or function, their effects in one or more in vitro, cellular, tissue, organ, or pharmacokinetics, pharmacodynamics, elimination, and the animal models. Such effects may be molecular, Supramolecu like. lar, cellular, tissue, organ, or whole-organism effects, or com 0182. It will be appreciated that these classifications are binations thereof. In some embodiments, drugs are classified exemplary only, and that any means of classifying drugs that based on their effects in one or more animal models together allows a non-random predictability of the effects of drugs in with associations between genotypes and response in the the class may be used. Further systems of drug classification animal models. For example, drug Amay cause response Min and specific drugs within each class may be found in the art. a mammal, e.g. a rat, mouse, or primate, of genotype X (e.g., See, e.g., Anderson, Philip O. Knoben, James E.; Troutman, genotype at one or more SNPs), and may cause response N in William G, eds., Handbook of Clinical Drug Data, Tenth a primate of genotype Y. If drug B is found to cause response Edition, McGraw-Hill, 2002: Pratt and Taylor, eds., Prin Min a mammal of genotype X and response N in a mammal ciples of Drug Action. Third Edition, Churchill Livingston, of genotype Y, then drug B is considered to be in the same New York, 1990; Katzung, ed., Basic and Clinical Pharma class as drug A. It will be appreciated that such classification cology, Ninth Edition, McGraw Hill, 20037ybg; Goodman may be greatly refined based on the number of genetic varia and Gilman, eds. The Pharmacological Basis of Therapeu tions included in the genotype, the number of responses mea tics, Tenth Edition, McGraw Hill, 2001, Remingtons Phar sured, and the like. The animal model allows a much wider maceutical Sciences, 20th Ed., Lippincott Williams & range of drugs to be tested, as well as more invasive param Wilkins., 2000; Martindale, The Extra Pharmacopoeia, eters to be measured as indications of response, and can allow Thirty-Second Edition (The Pharmaceutical Press, London, a much more extensive database to be established in a rela 1999); all of which are incorporated by reference herein in tively short time, compared to human testing. their entirety. 0179. In other embodiments, expression profiles for a drug 0183 Any suitable class of drugs for which genotyping in a model system may be used to classify the drug. For and association studies are possible for at least one member of example, all, most, or Some of the known drugs of a class of the class may be the subject of the described methods and drugs that has an effect in humans (e.g., statins that lower the compositions. Classes include the insulin sensitizers as risk of heart disease) may be tested in an animal model. described herein, e.g., PPAR modulators. Thus, in some Animals administered the drug may show consistent profiles embodiments, the invention provides a method for predicting of gene expression in response to the drug (e.g., increases in an individual's responsiveness to an insulin sensitizer, e.g., a expression of a gene or set of genes related to antiinflamma PPAR modulator based on the individual’s genotype (and/or tory activity). Other drugs of other classes may be tested in phenotype) and the results of association studies between animal models. The expression profiles associated with the genotype (and/or phenotype) and responsiveness to another drugs in a particular class may be correlated. A new drug may insulin sensitizer, e.g., PPAR modulator. In some embodi be assigned to a drug class based on its expression profile in ments, the prediction of an individual's responsiveness to an one or more animal models. The associations of one or more insulin sensitizer, e.g., PPAR modulator is used to include or drugs in that class between one or more genetic variations and exclude the individual in a clinical trial. In some embodi a response to the drug(s) may be used to modulate the use of ments, the prediction of an individual's responsiveness to an the new drug, for example, in research (e.g., clinical trials) insulin sensitizer, e.g., PPAR modulator is used to modulate and/or in the clinical setting. the individual's administration of another insulin sensitizer, 0180. In some embodiments, a new drug in a class of drugs e.g., PPAR modulator. In some embodiments such modula is first tested in a model, e.g. an animal model, in which other tion occurs in a clinical trial. In some embodiments, the drugs in the class of drugs have been tested, and in which a prediction of an individual’s responsiveness to an insulin genotype for the animal is used to predict responses to the sensitizer, e.g., PPAR modulator is used to determine that the new drug. The results of the animal studies can be used to individual should be treated with a drug other than an insulin refine predictions for the association between genetic varia sensitizer, or in some embodiments a PPAR modulator. tions and response to a new drug in humans. Animal models a. Mechanistic Classes of Drugs may be developed or existing animal models may be used. 0.184 One non-exclusive exemplary class of drugs for The animal model can be for a particular physiological, bio which genotyping (and/or phenotyping) and association stud chemical, or metabolic State, e.g., a disease or pathological ies with one member may be used to predict effects of another state. Healthy or superhealthy states may also be modeled member include, mechanistic classes of drugs used in the (e.g., decelerated aging). treatment of diabetes (including PPAR modulators). This 0181 Drugs may be further put into classes, or into sub class of drugs also illustrates how drugs can also be Sub classes of the same class, by classifications based on their classed by, e.g., mode of administration. For example, insulin mode administration (e.g., intravascular, intramuscular, Sub and insulin analogs may be formulated for administration by US 2008/0280955 A1 Nov. 13, 2008 25 injection, nasal spray, transdermal, oral or inhalation routes. classifications of Such drugs by mechanism, together with Each type of formulation can have unique profiles of representative members of the mechanistic classes, is given in responses and associated genetic variations. An example of Table 3.

TABLE 3 Classes of Drugs for Treatment of Diabetes Class Mechanism of Action Examples Peroxisome Target PPAR-gamma or PPAR-gamma and -alpha (see below). RosiglitaZone, PioglitaZone, Proliferator PPAR are nuclear receptors that help regulate glucose and lipid BalaglitaZone, see also Activated Receptor metabolism. Activation of PPAR-gamma improves insulin others described herein (PPAR) Agonists sensitivity and thus improves glycemic control. Dual-Action Act on both PPAR-gamma and PPAR-alpha. PPAR-alpha TAK-559, Muraglitazar, Peroxisome activation has effects on cellular uptake of fatty acids and their Tesaglitazar, Netoglitazone, Proliferator oxidation, and on lipoprotein metabolism. May also act to reduce See also others described Activated Receptor inflammatory response in vascular endothelial cells. herein Agonists Biguanidines Complete mechanism is not known. Reduces gluconeogenesis in Metformin, Metformin GR the liver by inhibiting glucose-6-phosphatase. Sulfonylureas Induce insulin Secretion by binding to cellular receptors that Glimepride, cause membrane depolarization and insulin exocytosis. Glyburide? glibenclamide, Glipizide, Gliclazide. Tobutamide Insulin and Insulin Supplements endogenous insulin. Insulin analogs have a variety Insulin lispro, Insulin aspart, Analogs (Injectable, of amino acid changes and have altered onset of action and Insulin glargine, Exubera, Inhaled, Oral, duration of action, as well as other properties, compared to native AERX Insulin Diabetes Transdermal, insulin. Inhaled insulin is absorbed through the alveoli. Spray Management System, HIM Intranasal) oral insulin is absorbed by the buccal mucosa and intranasal 2, Oaralin, Insulin detemir, through the nasal mucosa. Transdermal insulin is absorbed Insulin glulisine through the skin. Meglitinides Are thought to bind to a nonsulfonylurea beta cell receptor and Repaglinide, Nateglinide, act to cause insulin secretion by mechanism similar to Mitiglinide Sulfonylureas Alpha-Glucosidase Inhibit carbohydrate digestion. Act at brush border of intestinal Acarbose, Miglitol, Inhibitors epithelium. Voglibose Glucagon-Like Diabetic patients may lack native GLP-1, and anlalogs act as Exenatide, Exenatide LAR, Peptide(GLP)-1 Substitutes. GLP-1 is an intestinal peptide hormone that induces Liraglutide, ZP 10, Analogs glucose-dependent insulin secretion, controls gastric emptying, BN51077, inhibits appetite, and modulates secretion of glucagon and Somatostatin. Dipeptidyl Peptidase Inhibit DPP-IV, a ubiquitous enzyme that cleaves and inactivates LAF-237, p-32/98, MK (DPP)-IV Inhibitors GLP-1, thus inhibition of DPP-IV increases GLP-1 activity 431, P3298, NVP LAF 237, Pancreatic Lipase Inhibits lipases, thus inhibiting uptake of dietary fat. This causes Orlistat Inhibitors weight loss, improves insulin sensitivity and lowers hyperglycemia. Amylin Analogs Act to augment amylin, which acts with insulin by slowing Pramlintide glucose absorption from the gut and slows after-meal glucose release from liver. Dopamine D2 Thought to act to alleviate abnormal daily variations in central Bromocriptine receptor agonists neuroendocrine activity that can contribute to metabolic and immune system disordered. Immunosuppressants Suppress autoimmune response thought to be implicated in Daclizumab, NBI 6024, Type I and possibly Type II diabetes. Example: Humanized TRX-TolerRx, OKT3 monoclonal antibody that recognizes and inhibits the alpha gamma-1-ala-ala subunit of IL-2 receptors; humanized Mab that binds to T cell CD3 receptor to block function of T-effector cells that attack the body and cause autoimmune disease Insulin-like growth Recombinant protein complex of insulin-like growth factor-1 and Somatomedin-1 binding factor-1 agonists binding protein-3; regulates the delivery of somatomedin to target protein 3 tissues. Reduces insulitis severity and beta cell destruction Insulin sensitizers Insulin sensitizers, generally orally active S15261, Dexlipotam, CLX O901, R 483, TAK 654 Growth hormone Mimic the action of native GHR TH9507, SOM 230 releasing factor agonists Glucagon antagonists Inhibit glucagon action, stimulating insulin production and Liraglutide, NN 2501 Secretion, resulting in lower pos prandial glucose levels Diabetes type 1 Prevents destruction of pancreatic beta cells that occurs in type 1 Q-Vax, Damyd vaccine vaccine diabetes Sodium-glucose co Selectively inhibits the sodium g lucose co-transporter, which T 1095 transporter inhibitor mediates renal reabsorption and intestinal absorption of glucose to maintain appropriate blood glucose levels. Glycogen Inhibit glycogen phosphorylase, hus slowing release of glucose Ingliforib phosphorylase inhibitors US 2008/0280955 A1 Nov. 13, 2008 26

TABLE 3-continued Classes of Drugs for Treatment of Diabetes Class Mechanism of Action Examples Undefined Drugs that act in ways beneficial to those with Type I or Type II FK 614, INGAP Peptide, R mechanisms Diabetes Mellitus, e.g., by reducing blood glucose and 1439 triglyceride levels, whose mechanisms have not been elucidated. Antisense Bind to RNA and cause its destruction, thereby decreasing ISIS 113715 oligonucleotides protein production from corresponding gene. Insulinotropin Stimulate insulin release CJC 1131 agonists Gluconeogenesis Inhibit gluconeogenesis, thus modulating blood glucose levels CS 917 inhibitors Hydroxysteroid Inhibit hydroxysteroid dehydrogenase, which are responsible for BVT 3498 dehydrogenase excess glucocorticoid production and hence, visceral obesity inhibitors Beta 3 adrenoceptor Agonist for beta 3 adrenoceptor, decreases blood glucose and YM 178, Solabegron, agonist Suppresses weight gain N5984, Nitric oxide Decreases effects of NO NOX 700 antagonist Carnitine Inhibits carnitine palmitoyltransferase ST 1326 palmitoyltransferase inhibitor

0185. In other embodiments, mechanistic classes of drugs cholesterol acyltransferase inhibitors, peroxisome prolifera used in the treatment of abnormal cholesterol and/or triglyc tor activated receptor agonists, microsomal triglyceride pro eride levels in the blood are used in conjunction with a method or composition of the invention. Broad mechanistic classes tein inhibitors, squalene synthase inhibitors, lipoprotein include the statins, fibrates, cholesterol absorption inhibitors, lipase activators, lipoprotein (a) antagonists, and bile acid nicotinic acid derivatives, bile acid sequestrants, cholesteryl reabsorption inhibitors. An example of classification of Such ester transfer protein inhibitors, reverse lipid transport path drugs by mechanism, together with representative members way activators, antioxidants/vascular protectants, acyl-CoA of the mechanistic classes, is given in Table 4.

TABLE 4 Classes of Drugs for Treatment of Abnormal Cholesterol and/or Triglyceride Levels in the Blood Class Mechanism of Action Examples Statins Competitive inhibitors of HMG-CoA reductase Atorvastatin, Simvastatin, Pravastatin, Fluvastatin, Rosuvastatin, Lovastatin, Pitavastatin, Cerivastatin (withdrawn), Fibrates PPARC activators Fenofibrate, Bezafibrate, Gemfibrozil, clofibrate, ciprofibrate Cholesterol May inhibit NCP1L1 in gut Ezetimibe Absorption Inhibitors Nicotinic Acid inhibits cholesterol and triglyceride synthesis, exact mechanism Niacin Derivatives unknown Bile Acid interrupt the enterohepatic circulation of bile acids Colesevelam, Sequestrants Cholestyramine, Colestimide, Colestipol Cholesteryl Ester inhibit cholesteryl ester transfer protein, a plasma protein that JTT-705, CETi-1, Transfer Protein mediates the exchange of cholesteryl esters from antiatherogenic Torcetrapib Inhibitors HDL to proatherogenic apoliprotein B-containing lipoproteins Reverse Lipid Stimulate reverse lipid transport, a four-step process form ETC-216, ETC-588, ETC Transport Pathway removing excess cholesterol and other lipids from the walls of 642, ETC-1001, ESP-1552, Activators arteries and other tissues ESP-24232 Antioxidants. Vascular inhibit vascular inflammation and reduce cholesterol levels: AGI-1067, Probucol Protectants block oxidant signals that Switch on vascular cellular adhesion (withdrawn) molecule (VCAM)-1 Acyl-CoA inhibit ACAT, which catalyzes cholesterol esterification, Eflucimibe, Pactimibe, Cholesterol regulates intracellular free cholesterol, and promotes cholesterol Avasimibe (withdrawn), Acyltransferase absorption and assemble of VLDL SMP-797 (ACAT) Inhibitors Peroxisome Activate PPARs, e.g., PPARC, Y, and possibly 8, which have a Tesaglitazar, GW-50516, Proliferator Activated variety of gene regulatory functions GW-590735, LY-929, LY Receptor Agonists 518674, LY-465608, LY. 818 US 2008/0280955 A1 Nov. 13, 2008 27

TABLE 4-continued Classes of Drugs for Treatment of Abnormal Cholesterol and/or Triglyceride Levels in the Blood Class Mechanism of Action Examples Microsomal Inhibit MTTP, which catalyze the transport of triglycerides, Implitapide, CP-346086 Triglyceride Transfer cholesteryl ester, and phosphatidylcholine between membranes; Protein (MTTP) required for the synthesis of ApoB. Inhibitors Squalene Synthase Interfere with cholesterol synthesis by halting the action of liver TAK-475, ER-1198.84 Inhibitors enzymes; may also slow or stop the proliferation of several cell types that contribute to atherosclerotic plaque formation Lipoprotein Lipase Directly activate lipoprotein lipase, which promotes the Ibrolipim (NO-1886) Activators breakdown of the fat portion of lipoproteins Liproprotein(a) Not yet established Gembacene Antagonists Bile Acid Inhibit intestinal epithelial uptake of bile acids. AZD-7806, BARI-1453, S Reabsorption 8921 Inhibitors

0186. In other embodiments, mechanistic classes of drugs oxidase inhibitors (MAOIs), noradrenergic/dopaminergic used in the treatment of depression are used in conjunction agents, serotoninantagonists, serotoninagonists, Substance P with a method or composition of the invention. Current or emerging antidepressant drugs act by a variety of mecha antagonists, and beta adrenoreceptor agonists. An example nisms, e.g., selective serotonin reuptake inhibitors (SSRIs), of classification of Such drugs by mechanism, together with serotonergic/noradrenergic agents, serotonin/noradrenergic/ representative members of the mechanistic classes, is given in dopaminergic agents, tricyclic antidepressants, monoamine Table 5.

TABLE 5 Classes of Drugs for Treatment of depression Class Mechanism of Action Examples Selective Serotonin Block presynaptic reuptake of serotonin. Exert little effect on Escitallopram, Sertraline, Reuptake Inhibitor norepinephrine or dopamine reuptake. Level of serotonin in Citalopram, Paroxetine, (SSRI) the synaptic cleft is increased. Paroxetin, controlled release, Fluoxetine, Fluoxetine weekly, Fluvoxamine, olanzapine/fluoxetine combination Serotonergic/noradrenergic Inhibit both serotonin reuptake and norepinephrine reuptake. Venlafaxine: Reboxetine, agents Different drugs in this class can inhibit each receptor to Milnacipran, Mirtazapine, different degrees. Do not affect histamine, acetylcholine, and Nefazodone, Duloxetine adrenergic receptors. Serotonergic/noradrenergic Several different mechanisms. Block norepinephrine, Bupropion, Maprotiline, dopaminergic agents Serotonin, and/or dopamine reuptake. Some have addictive Mianserin, Trazodone, potential due to dopamine reuptake inhibition. Dexmethylphenidate, Methyphenidate, Amineptine Tricyclic Antidepressants Block synaptic reuptake of serotonin and norepinephrine. Amitriptyline, Amoxapine, Have little effect on dopamine. Strong blockers of Clomipramine, muscarinic, histaminergic H1, and alpha-1-adrenergic Desipramine, Doxepin, receptors. Imipramine, Nortriptyline, Protriptyline, Trimipramine Irreversible Monoamine Monoamine oxidase (MAO) metabolizes monoamines such as Isocarboxazid, Phenelzine, Oxidase Inhibitors serotonin and norepinephrine. MAO inhibitors inhibit MAO, Tranylcypromine, thus increasing levels of serotonin and norepinephrine. Transdermal Selegiline Reversible Monoamine See above. Short acting, reversible inhibitor, inhibits Moclobemide Oxidase Inhibitors deamination of serotonin, norepinephrine, and dopamine. Serotonergic/noradrenergic Act to block all of Serotonin, norepinephrine, and dopamine DOV-216303, DOV-21947 dopaminergic reuptake reuptake. May have addictive potential due to dopamine inhibitors reuptake inhibition. Noradrenergic dopaminergic Block reuptake of norepinephrine and dopamine GW-353.162 agents Serotonin Antagonists Selective antagonist of one serotonin receptor (the 5-HT Agomelatine receptor) Serotonin Agonists Partial agonist of the 5-HT1A receptor. Eptapirone, Vilazodone, OPC-14523, MKC-242, Gepirone ER US 2008/0280955 A1 Nov. 13, 2008 28

TABLE 5-continued Classes of Drugs for Treatment of depression Class Mechanism of Action Examples Substance P Antagonists Modify levels of substance P, which is released during acute Aprepitant, TAK-637, CP StreSS. 122721, E6006, R-763OPC GW-5975.99 Beta Adrenoreceptor Indirectly inhibit norepinephrine reuptake. Also being SR-58611 Agonists investigated for treatment of obesity and diabetes because they stimulate lipolysis and thermogenesis.

0187. In other embodiments, mechanistic classes of drugs chemokine receptor antagonists, AMPA receptorantagonists, used in the treatment of multiple Sclerosis are used in con recombinant human glial growth factors, T-cell receptor vac junction with a method or composition of the invention. These drugs can be classed as, e.g., recombinant interferons, cines, and oral immunomodulators. An example of classifi altered peptide ligands, chemotherapeutic agents, immuno cation of Such drugs by mechanism, together with represen Suppressants, corticosteroids, monoclonal antibodies, tative members of the mechanistic classes, is given in Table 6.

TABLE 6 Classes of Drugs for Treatment of Multiple Sclerosis Class Mechanism of Action Examples Recombinant IFN-beta has numerous effects on the immune system. Exact Interferon-beta-1b, interferons mechanism of action in MS not known Interferon-beta-1a Altered peptide Ligands either templated on sequence of myelin basic protein, or Glatiramer acetate, MBP ligands containing randomly arranged amino acids (e.g., ala, lys, glu, tyr) 8298, Tiplimotide, AG-284 whose structure resembles myelin basic protein, which is thought to be an antigen that plays a role in MS. Bind to the T-cell receptor but do not activate the T-cell because are not presented by an antigen-presenting cell. Chemotherapeutic Immunosuppressive. MS is thought to be an autoimmune Mitoxantrone, agents disease, so chemotherapeutics that Suppress immunity improve Methotrexate, MS Cyclophosphamide Immunosuppressants Act via a variety of mechanisms to dampen immune response. Azathioprine, Teriflunomide, Oral Cladribine Corticosteroids Induce T-cell death and may up-regulate expression of adhesion Methylprednisolone molecules in endothelial cells lining the walls of cerebral vessels, as well as decreasing CNS inflammation. Monoclonal Bind to specific targets in the autoimmune cascade that produces Natalizumab, Daclizumab, Antibodies MS, e.g., bind to activated T-cells Altemtuzumab, BMS 188667, E-6040, Rituximab, M1 MAbs, ABT 874, T OO47 Chemokine Receptor Prevent chemokines from binding to specific chemokine BX-471, MLN-3897, MLN Antagonists receptors involved in the attraction of immune cells into the CNS 12O2 of multiple Sclerosis patients, and inhibiting immune cell migration into the CNS AMPA Receptor AMPA receptors bind glutamate, an excitatory neurotransmitter, E-2007 Antagonists which is released in excessive quantities in MS. AMPA antagonists Suppresses the damage caused by the glutamate Recombinant Human GGF is associated with the promotion and Survival of Recombinant Human GGF2 Glial Growth Factor oligodendrocytes, which myelinate neurons of the CNS. rhGGF (GGF) may help myelinate oligodendrocytes and protect the myelin sheath. T-cell Receptor Mimic the part of the receptor in T cells that attack myelin NeuroVax Vaccine sheath, which activates regulatory T cells to decrease pathogenic T-cells. Oral Various effects on the immune response that can modulate the Simvastatin, FTY720, Oral Immunomodulators process of MS Glatiramer Acetate, FTY 720, Pirfenidone, Laquinimod US 2008/0280955 A1 Nov. 13, 2008 29

0188 In other embodiments, mechanistic classes of drugs classified by structure. Non-exclusive examples of drug used in the treatment of Parkinson's disease are used in con classes useful in the methods and compositions of the inven junction with a method or composition of the invention. tion, and representative members of these classes, include: These classes include dopamine precursors, dopamine ago 0191 Sedative-Hypnotic Drugs, which include drugs that nists, COMT inhibitors, MAO-B inhibitors, antiglutameter bind to the GABA receptor such as the benzodiazepines gic agents, anticholinergic agents, mixed dopaminergic (including alprazolam, chlordiazepoxide, cloraZepate, clon agents, adenosine A2a antagonists, alpha-2 adrenergic azepam, diazepam, estaZolam, flurazepam, halazepam, antagonists, antiapoptotic agents, growth factor Stimulators, lorazepam, midazolam, oxazepam, quaZepam, temazepam, and cell replacements. An example of classification of Such triazolam), the barbiturates (such as amobarbital, pentobar drugs by mechanism, together with representative members bital, phenobarbital, secobarbita), and non-benzodiazepines of the mechanistic classes, is given in Table 7. (such as Zolpidem and Zaleplon), as well as the benzodiaz

TABLE 7 Classes of Drugs for Treatment of Parkinson's Disease Class Mechanism of Action Examples Dopamine Precursors Act as precursors in the synthesis of dopamine, the Levodopa, Levodopa neurotransmitter that is depleted in Parkinson's Disease. Usually carbidopa, Levodopa administered in combination with an inhibitor of the carboxylase benserazide, Etilevodopa, enzyme that metabolizes levodopa. Some (e.g., Duodopa) are Duodopa given by infusion, e.g., intraduodenal infusion Dopamine Agonists Mimic natural dopamine by directly stimulating striatal dopamine Bromocriptine, Cabergoline, receptors. May be subclassed by which of the five known Lisuride, Pergolide, dopamine receptor Subtypes the drug activates; generally most Pramipexole, Ropinirole, effective are those that activate receptors the in the D2 receptor Talipexole, Apomorphine, family (specifically D2 and D3 receptors). Some are formulated Dihydroergocryptine, for more controlled release or transdermal delivery. Lisuride, Piribedil, Talipexole, Rotigotin CDS, Sumanirole, SLV-308 COMT Inhibitors Inhibits COMT, he second major enzyme that metabolized Entacapone, Tolcapone, levodopa. Entacapone-Levodopa Carbidopa fixed combination, MAO-B Inhibitors MAO-B metabolizes dopamine, and inhibitors of MAO-B thus Selegiline, Rasagiline, prolong dopamines half-life Safinamide Antiglutamatergic Block glutamate release. Reduce levodopa-induced dyskinesia Amantadine, Budipine, Agents Talampanel, Zonisamide Anticholinergic Thought to inhibit excessive cholinergic activity that Trihexyphenidyl, Agents accompanies dopamine deficiency Benztropine, Biperiden Mixed Dopaminergic Act on several neurotransmitter systems, both dopaminergic and NS-2330, Sarizotan Agents nondopaminergic. Adenosine A2a Adenosine A2 antagonize dopamine receptors and are found in Istradefylline antagonists conjunction with dopamine receptors. Antagonists of these receptors may enhance the activity of dopamine receptors. Alpha-2Adrenergic Not known. Yohimbine, Idazoxan, Antagonists Fipamezole Antiapoptotic Agents Can slow the death of cells associated with the neurodegenerative CEP-1347, TCH-346 process of Parkinson's disease. Growth Factor Promote the Survival and growth of dopaminergic cells. GPI-1485, Glial-cell-line Stimulators derived Neurotrophic Factor, SR-57667, PYM SOO28 Cell Replacement Replace damaged neurons with health neurons. Spheramine Therapy

0189 The above classifications are exemplary only. It will epine antagonists (such as flumazenil). Other sedative-hyp be appreciated that a drug class need not be restricted to drugs notic drugs appear to work through non-GABA-ergic mecha used in the treatment of a single disease, but that a given nisms such as through interaction with serotonin and mechanistic class may have members useful in the treatment dopaminergic receptors, and include buspirone, isapirone, of a number of diseases. Fora example, MAO-B inhibitors are geprinone, and tandospirone. Older drugs work through useful in the treatment of both Parkinson's disease and mechanisms that are not clearly elucidated, and include chlo depression; as another example, statins are useful in the treat ral hydrate, ethchlorVynol, meprobamate, and paraldehyde. ment of dyslipidemias but are also being found to have more 0.192 In some embodiments, sedative-hypnotic drugs that general use in diseases where inflammation plays a major interact with the GABA receptor, such as benzodiazepines role, e.g., multiple Sclerosis and other diseases. and non-benzodiazepines, are further classified as to which 0190. Further classifications of drugs by mechanism are subunit or subunits of the GABA receptor that they interact known in the art; often these classifications may be further with, e.g., the C. (which is further classified into six Subtypes, US 2008/0280955 A1 Nov. 13, 2008 30 including C-1.2.3, and 5), B (further classified as four differ cetrizine, chlorpheniramine, clemastine, cyclizine, cyprohep ent types), Y (three different types), Ö, e, t, p, etc. Such a tadine, desloratidine, dimenhydrinate, diphenhydramine, classification can allow further refinement of associations emedastine, fexofenadine, hydroxy Zine, ketotifen, levo between genetic variation and responsiveness to a given seda cabastine, loratadine, meclizine, olopatadine, phenindamine, tive-hypnotic that interacts with a particular Subclass, and and promoathazine. predictions for a new sedative-hypnotic that interacts with the 0.196 Drugs used in asthma include sympatheticomimet same Subclass of receptors. ics (used as “relievers,” or bronchodilators) such as albuterol, 0193 Opioid analgesics and antagonists act on the opioid albuterol/lpratropium, bitolterol, ephedrine, epinephrine, for receptor. The majority of currently available opioid analge moterol, isoetharine, isoproterenol, levalbuterol, metaproter sics act primarily at the L opioid receptor. However, interac enol, pirbuterol, salmeterol, salmeterol/fluticasone, terbuta tions also occur with the 8 and K receptors. Similar to the line; aerosol corticosteroids (used as “controllers.” or sedative-hypnotics, in Some embodiments opioid analgesics antiinflammatory agents) such as beclomethasone, budes are further classed as to subtypes of receptors at which they onide, flunisolide, fluticaSone, fluticasone/salmeterol, triam primarily interact, thus allowing further refinement of the cinolone; leukotriene inhibitors such as montelukast, association between drug response and genetic variation, and Zafirlukast, Zileuton; cormolyn Sodium and nedocromil higher predictability for a new drug, based on which receptor Sodium; methylxanthines Such as aminophylline, theophyl (s) it interacts with. Opioid analgesics include alfentanil, linem dyphylline, oxtriphylline, pentoxifylline; antimuscar buprenorphine, butorphanol, codeine, dezocine, fentanyl. inic drugs such as ipratropium; and antibodies such as oma hydromorphone, levomethadyl acetate, levorphanol, meperi lizumab. dine, methadone, morphine Sulfate, nalbuphine, oxycodone, 0.197 Erectile dysfunction drugs include c0MP enhanc oxymorphone, pentazocine, propoxyphene, remifentanil, erS Such as sildenafil (Viagra), tadalafil. Vardenafil, and Sufentanil, tramadol; analgesic combinations such as alprostadil, and dopamine releasers such as apomorphine codeinefacetaminophen, codeine/aspirin, hydrocodone?ac 0198 Drugs used in the treatment of gastrointestinal dis etaminophen, hydrocodone/ibuprofen, oxycodonefacetami ease act by a number of mechanisms. Drugs that counteract nophen, oxycodone/aspirin, propoxyphene/aspirin or acidity (antacids) include aluminum hydroxide gel, calcium acetaminophen. Opioid antagonists include nalmefene, carbonate, combination aluminum hydroxide and magne naloxone, naltrexone. Antitussives include codeine, dex sium hydroxide preparation. Drugs that act as proton pump tromethorphan. inhibitors include esomeprazole, lanSoprazole, pantoprazole, 0194 Nonsteroidal anti-inflammatory drugs act primarily and rabeprazole. H2 histamine blockers include cimetidine, through inhibition of the synthesis of prostaglandins, e.g., famotidine, nizatidine, ranitidine. Anticholinergic drugs through inhibition of COX-1, COX-2, or both. Older include atropine, belladonna alkaloids tincture, dicyclomine, NSAIDS (e.g. salicylates) tend to be non-selective as to the glycopyrrolate, I-hyoscyamine, methScopolamine, propan type of COX inhibited, whereas newer drugs are quite selec theline, scopolamine, tridihexethyl. Mucosal protective tive (e.g., the COX-2 inhibitors). Non-selective COX inhibi agents include misoprostol. Sucralfate. Digestive enzymes tors include aspirin, acetylsalicylic acid, choline Salicylate, include pancrelipase. Drugs for motility disorders and anti diclofenac, etodolac, fenoprofen, flurbiprofen, ibuprofen, emetics include alosetron, cisapride, dolasetron, dronabinol, indomethacin, ketoprofen, ketorolac, magnesium salicylate, granisetron, metoclopramide, ondansetron, prochlorpera meclofenamate, mefenamic acid, nabumetone, naproxen, Zine, tegaserod. Antiinflammatory drugs used in gastrointes oxaprozin, phenylbutaZone, piroXicam, Salsalate, Salicylsali tinal disease include balsalazide, budesonide, hydrocorti cylic acid, Sodium salicylate, Sodium thiosalicylate, Sulindac, SOne, mesalamine, methylprednisone, olsalazine, tenoxicam, tiaproven, azapropaZone, carprofen, and tol Sulfasalazine, infliximab. Antidiarrheal drugs include bis metin. Selective COX-2 inhibitors include celecoxib, etrori muth Subsalicylate, difenoxin, diphenoxylate, kaolin?pectin, coxib, meloxicam, rofecoxib, and Valdecoxib. loperamide. Laxative drugs include bisacodyl, cascara 0.195 Histamine agonists and antagonists are classified Sagrada, castor oil, docusate, glycerin liquid, lactulose, mag according to receptor Subtype. Hagonists or partial agonists nesium hydroxide milk of magnesia, Epson Salt, methyl include 2-(m-fluorophenyl)-histamine and antagonists cellulose, mineral oil, polycarbophpil, polyethylene glycol include chlorpheniramine, Scopolamine, mepyramine, ter electrolyte Solution, psyllium, Sienna. Drugs that dissolve fenadine, astemizole, and triprolidine; further antagonists gallstones include monoctanoin, ursodiol. (which may be further classified by their chemical structures) 0199 Cholinoceptor-activating drugs, which act by acti include the ethanolamines carbinoxamine, dimenhydrinate, Vating muscarinic and/or nicotinic receptors include esters of diphenhydramine, and doxylamine; the ethylaminediamines choline (e.g., acetylcholine, metacholine, carbamic acid, car pyrilamine and tripelennamine; the piperazine derivatives bachol, and bethanechol) and alkaloids (e.g., muscarine, pilo dydroxy Zine, cyclizine, feXofenadine and meclizine; the carpine, lobeline, and nicotine); cholinesterase-inhibiting alkylamines brompheniramine and chlorpheniramine; and drugs which typically act on the active site of cholinesterase miscellaneous antagonists cyproheptadine, loratadine, cetriz include alcohols bearing a quaternary ammonium group (e.g., ine. He agonists include dimaprit, impromidine, and edrophonium), carbamates and related agents (e.g., neostig amthamine; and antagonists (useful in the treatment of gastric mine, physostigmine, pyridostigmine, ambenonium, and acid secretion) include cimetidine, ranitidine, nizatidine, and demercarium), and organic derivatives of phosphoric acid famotidine; H agonists include R-alpha-methylhistamine, (e.g., echothiophate, Soman, parthion, malathion); choli imetit, and immepip and antagonists include thioperamide, noceptor-blocking drugs typically act as antagonists to nico iodophenpropit, and clobenpropit; and H agonists include tinic receptors (further classified as ganglion-blockers. Such clobenpropit, imetit, and clozapine and antagonists include as hexamethonium, mecmylamine, teteraethylammonium, thioperamide. Available preparations include the H1 blockers and trimethaphan; and neuromuscular junction blockers, see aZelastine, brompheniramine, buclizine, carbinoxamine, skeletal muscle relaxants) or antagonists to muscarinic recep US 2008/0280955 A1 Nov. 13, 2008 tors (e.g. atropine, propantheline, glycopyrrolate, piren ics, and potassium sparing diuretics; drugs that act on the Zepine, dicyclomine, tropicamide, ipatropium, banztropine, central nervous system such as methyldopa and clonidine; gallamine, methooctramine, AF-DX 116, telenzipine, trihex ganglion-blocking drugs, Suprea; adrenergic neuron-block yphenidyl, darifenacin, Scopolamine, homatropine, cyclo ing agents such as gunethidine, gunadrel, bethanidine, pentolate, anisotropine, clidinium, isopropamide, mepen debrisoquin, and reserpine; adrenoceptor antagonists such as Zolate, methScopolamine, oxyphenonium, propantheline, propanolol, metoprolol, nadolol, carteolol, atenolol, betax oxybutynin, oxyphencyclimine, propiverine, tolterodine, olol, bisoprolol, pindolol, acebutolol, and penbutolol, labe tridihexethyl), which can be further subclassed as to which talol, carvedilol, esmolol, paZosin, phentolamine and phe muscarinic receptor is the primary site of the effect, e.g., M. M. M. M. or Ms., allowing greater predictability for an noxybenzamine; vasodilators such as hydralzaine, minoxidil, association between a genetic variation and a response for a Sodium nitroprusside, diazoxide, fenoldopam, and calcium new drug based on its primary site of effect. Available prepa channel blockers (e.g., Verapamil, diltiazem, amlopidine, rations of antimuscarinic drugs include but are not limited to felopidine, isradipine, nicardipine, nifedipine, and nisol atropine; beladonna alkaloids, extract, or tincture; clidinium; dipine); ACE-inhibitors such as captropril, enalapril, lisino cyclopentolate; dicyclomine; flavoxate; glycopyrrolate; pril, benazepril, fosinopril, moexipril, perindopril, quinapril, homatropine, 1-hysocyamine, ipratropium; mepenZolate; ramipril, and trandolapril; angiotensin receptor blocking methantheline; methScopolamine; oxybtynin, prpantehline; agents such as losartan, Valsartan, candesartan, eprosartan, Scopolamine; tolterodine; tridihexethyl, tropicamide. Avail irbesartan, and telmisartan. Preparations available include: able preparations of ganglion blockers include mecamy beta adrenoceptor blockers acebutolol, atenolol, betaxolol, lamine and trimethaphan. Available cholinesterase regenera bisoprolol, carteolol, carvedilol, exmolol, labetalol, meto tors include pralidoxime. prolol, nadolol, penbutolol, pindolol, propanolol, timolol; 0200 Adrenoceptor-activating drugs and other sympatho centrally acting sympathoplegic drugs clonidine, gunabenz, mimetic drugs may be classified according to the receptor or guanfacine, methyldopa; postganglionic sympatheic nerve receptors that they activate, e.g., alpha-one type (including terminal blockers gunadrel, guanethidine, and reserpine; Subtypes A, B, D), alpha-two type (including Subtypes A, B, alpha one selective adrenoceptor blockers doxazosin, pra and C), beta type (including Subtypes 1, 2, and 3), and dopam Zosin, teraZosin; ganglion-blocking agent mecamylamine; ine type (including Subtypes 1,2,3,4, and 5. Exemplary drugs vasodilators diaZOxide, fenoldopam, hydralazine, minoxidil, include epinephrine, norepinephrine, phenylephrine, meth nitroprusside; calcium channel blockers amlodipine, dilt oxamine, milodrine, ephedrine, Xylometazoline, amphet iazem, felodipine, isradipine, nicardipine, nisoldipine, nife amine, methamphetamine, phenmetrazine, methylphenidate, dipine, Verapamil: ACE inhibitors benazepril, captopril, phenylpropanolamine, methylnorepinephrine, dobutamine, enalapril, fosinopril, lisinopril, moexipril, perindopril, clonidine, BHT920, oxymetazoline, isoproterenol, pro quinapril, ramipril, and trandolapril; and angiotensin receptor caterol, terbutaline, metaproterenol, albuterol, ritodrine, BRL37344, dopamine, fenoldopam, bromocriptine, quin blockers candesartan, eprosartan, irbeartan, losartan, olmis pirol, dexmedetomidine, tyramine, cocaine (dopamine artan, telmisartan, and Valsartan. reuptake inhibitor), apraclonidine, brimonidine, ritodrine, 0203 Vasodilators used in angina pectoris include nitric terbutaline, and modafinil. Available preparations include oxide releasing drugs such as nitric and nitrous acid esters of amphetamine, apraclonidine, brimonidine, dexmedetomi polyalcohols such as nitroglycerin, isorbide dinitrate, amyl dine, dexmthylphenidate, dextroamphetamine, diplivefrin, nitrite, and isosorbide mononitrate; calcium channel blockers dobutamine, dopamine, ephedrine, epinephrine, fenoldopam, Such as amlodipine, felodipine, isradipine, nicardipine, nife hydroxyamphetamine, isoproterenol, mephentermine, met dipine, nimodipine, nisoldipine, nitrendipine, bepridil, dilt araminol, methamphetamine, methoxamine, methylpheni iazem, and Verapamil; and beta-adrenoceptor-blocking drugs date, midodrine, modafinil, naphazoline, norepinephrine, (see above). Available preparations include: nitrates and oxymetzoline, pemoine, phendimetrazine, phenylephrine, nitrites amyl nitrite, isosorbide dinitrate, isosorbide mononi pseudoephedrine, tetrahydrozoline, and Xylometaoline. trate, nitroglycerin; calcium channel blockers amlodipine 0201 Adrenoceptor antagonist drugs may be classified by bepridil, diltiazem, felodipine, isradipine, nicardipine, nife receptor Type In the same manner as adrenoceptor agonists, dipine, nimodipine, nisoldipine, and Verapamil; and beta and include tolaZoline, dibenamine, praZosin, teraZosin, dox blockers acebutolol, atenolol, betaxolol, bisoprolol, car aZosin, phenoxybenzamine, phentolamine, rauwoscine, teolol, carvedilol, esmolol, labetolol, levobunolol, yohimbine, labetalol, carvedilol, metoprololol, acebutolol. metiproanolol, nadolol, penbutolol, pinolol, propanolol. alprenolol, atenolol, betaxolol, celiprolol, esmolol, pro Sotalol, timolol. panolol, carteolol, penbutolol, pindolol, timolol, butoxamine, 0204 Drugs used in heart failure include cardiac glyco ergotamine, dihydroergotamine, tamulosin, alfuZosin, sides such as digoxin; phosphodiesterase inhibitors such as indoramin, urapidil, bisoprolol, nadolol, Sotalol, oxpenolol. inmrinone and milrinone; beta adrenoceptor stimulant Such bopindolol, medroxalol, and bucindolol. Available prepara as those described: diuretics as discussed below; ACE inhibi tions include: alpha blockers doxazosin, phenoxybenzamine, tors such as those discussed above; drugs that inhibit both phentolamine, praZosin, tamsulosin, teraZosin, and tolaZo ACE and neutral endopeptidase Such as omaprtrilat, vasodi line; and beta blockers acebutolol, atenolol, betaxolol, biso lators such as synthetic brain natriuretic peptide (nesiritide) prolol, carteolol, carvedilol, esmolol, labetolol, levobunolol. and bosentan; beta adrenoceptor blockers such as those metiproanolol, nadolol, penbutolol, pinolol, propanolol. described above. Available preparations include: digitalis Sotalol, timolol; and synthesis inhibitor metyrosine. digoxin; digitalis antibody digoxin immune Fab., sympatho 0202 Antihypertensive agents include drugs that work by mimetics dobutamine and dopamine; ACE inhibitors capto a variety of mechanisms and thus overlap with other classifi pril, enalapril, fosinopril, lisinopril, quinapril, ramipril, and cations. Agents can include diuretics such as thiazide diuret trandolapril; angiotensin receptor blockers candesartan, US 2008/0280955 A1 Nov. 13, 2008 32 wprosartan, irbesartan, losartan, olmesartan, telmisartan, and 0209 Vasoactive Peptides include aprepitant, bosentan. Valsartan; beta blockers bisoprolol, carvedilol, and meto 0210 Eicosanoids include prostaglandins, thomboxanes, prolol. and leukotrienes. Eicosanoid modulator drugs include alpros 0205 Cardiac arrhythmia drugs include drugs that act by tadil, bimatoprost, carboprost tromethamine, dinoprostone, blocking Sodium channels such as quinidine, amiodaron, epoprostenol, latanoprost, misoprostol, monteleukast, disoprymide, flecamide, lidocaine, mexiletine, morcizine, travaprost, treprostinil, unoprostone, Zafirleukast, Zileuton. procainamide, propafeneone, and tocamide; beta-adrenocep Further eicosanoid modulators are discussed elsewhere tor-blocking drugs such as propanolol, esmolol, and Sotalol; herein as nonsteroidal antiinflammatory drugs (NSAIDs) 0211 Drugs for the treatment of acute alcohol withdrawal drugs that prolong the effective refractory period by prolong include diazepam, lorazepam, oxazepam, thiamine; drugs for ing the action potential Such as amiodarone, bretylium, prevention of alcohol abuse include disulfuram, naltrexone; Sotalol, dolfetilide, and ibutilide; calcium channel blockers and drugs for the treatment of acute methanol or ethylene Such as Verapamil, diltizem, and bepridil; and miscellaneous glycol poisoning include ethanol, fomepizole. agents such as adenosine, digitalis, magnesium, and potas 0212 Antiseizure drugs include carbamazepine, clon sium. Available preparations include: the sodium channel azepam, cloraZepate dipotassium, diazepam, ethoSuximide, blockers disopryamide, flecamide, lidocaine, miexiletine, ethotoin, felbamate, fosphenytoin, gabapentin, lamotrigine, moricizine, procainamide, propafenone, quinidine Sulfate, levetiracetam, lorazepam, mephenyloin, mephobarbital, oxy quinidine gluconate, and quinidine polygalacturonate; the carbazepine, pentobarbital Sodium, phenobarbital, pheny beta blockers acebutolol, esmolol, and propranolol; the action loin, primidone, tiagabine, topiramate, trimethadione, Valp potential-prolonging agents amiodarone, bretylium, dolfetil roic acid. ide, ibutilide, and sotalol; the calcium channel blockers bepri 0213 General anesthetics include desflurane, dexmedeto dil, diltiazem, and Verapamil; and adenosine and magnesium midine, diazepam, droperidol, enflurane, etomidate, hal sulfate. othane, isoflurane, ketamine, lorazepam, methohexital, meth 0206 Diuretic agents include drugs that act as carbonic oxyflurane, midazolam, nitrous oxide, propofol, sevoflurane, anhydrase inhibitors such as acetazoloamide, dichlorphena thiopental. mide, methazolamide; loop diuretics Such as furosemide, 0214 Local anesthetics include articaine, benzocaine, bumetanide, torsemide, ethacrynic acid, and mercurial bupivacaine, butamben picrate, chloroprocaine, cocaine, diuretics; drugs that inhibit NaCl transport in the distal con dibucaine, dyclonine, levobupivacaine, lidocaine, lidocaine voluted tubule and, in some cases, also act as carbonic anhy and etidocaine eutectic mixture, mepivacaine, pramoxine, drase inhibitors, such as bendroflumethiazide, benzthiazide, prilocalne, procaine, proparacaine, ropivacaine, tetracaine. chlorothiazide, chlorthalidone, hydrochlorothiazide, hydrof 0215 Skeletal muscle relaxants include neuromuscular lumethiazide, indapamide, methyclothiazide, metolaZone, blocking drugs such as atracurium, cisatracurium, doxacu polythiazide, quinethaZone, and trichlormethaZide; potas rium, metocurine, mivacurium, pancuronium, pipecuronium, sium-sparing diuretics such as spironolactone, triamterene, rocuronium, Succinylcholine, tubocurarine, Vecuronium; eplerenone, and amiloride; osmotic diuretics such as manni muscle relaxants (spasmolytics) such as baclofen, botulinum tol; antidiuretic hormone agonists such as vasopressin and toxin type A, botulinum toxin type B, carisoprodol, chorphen desmopressin; antidiuretic hormone antagonists Such esin, chlorZoxazone, cyclobenzaprine, dantrolene, diazepam, aslithium and demeclocycline. Available preparations gabapentin, metaxalone, methocarbamol, orphenadrine, rilu include actetazolamide, amiloride, bendroflumethiazide, Zole, and tizanidine. benzthiazide, brinzolamide, bumetanide, chlorothiazide, 0216 Antipsychotic agents include aripiprazole, chlor chlorthalidone, demeclocycline, dichlorphenamide, dorZola promazine, clozapine, fluphenazine, fluiphenazine esters, mide, eplerenone, ethacrynic acid, furosemide, hydrochlo haloperidol, haloperidol ester, loxapine, mesoridazine, rothiazide, hydroflumethiazide, indapamide, mannitol, met molindone, olanzapine, perphenazine, pimozide, prochlor haZolamide, methyclothiazide, metolaZone, polythiazide, perazine, promazine, quetiapine, risperidone, thioridazine, quinethaZone, apironolactone, torsemide, triamterene, and thiothixene, trifluoperazine, triflupromazine, Ziprasidone; trichlormethiazide. mood stabilizers include carbamazepine, divalproex, lithium 0207 Serotonin and drugs that affect serotonin include carbonate, and valproic acid. serotoninagonists such as fenfluramine and dexfenfluramine, 0217 Agents used in anemias include hematopoietic buspirone, Sumatriptan, cisapride, tegaserod; seratonin growth factors such as darbopoetin alfa, deferoxamine, epo antagonists p-chlorophenylalanine and p-chloroamphet etin alfa (erythropoetin, epo), filgrastim (G-CSF), folic acid, amine, and reserpine; and the serotonin receptor antagonists iron, oprelvekin (interleukin-11), pegfilgrastim, sargra phenoxybenzamine, cyproheptadine, ketanserin, ritanserin, mostim (GM-CSF), vitamin B. and ondansetron; serotonin reuptake inhibitors are described 0218. Disease-modifying antirheumatic drugs include elsewhere herein. Serotonin receptor agonists include almot anakinra, adalimumab, auranofin, aurothioglucose, etaner riptan, eletriptan, froVatriptan, naratriptan, rizatriptan, cept, gold sodium thiomalate, hydroxychloroquine, inflix Sumatriptan, and Zolmitriptan. imab, leflunomide, methotrexate, penicillamine, Sulfasala 0208 Ergot alkaloids are useful in the treatment of, e.g., Zine. Drugs used in gout include allopurinol, colchicine, migraine headache, and act on a variety of targets, including probenecid, Sulfinpyrazone. alpha adrenoceptors, serotonin receptors, and dopamine 0219 Drugs used in disorders of coagulation include receptors. They include bromocriptine, cabergoline, per abciximab, alteplase recombinant, aminocaproic acid, anis golide, ergonovine, ergotamine, lysergic acid diethylamide, indione, antihemophilic factor factor VIII, AHF, anti-in and methysergide. Available preparations include dihydroer hibitor coagulant complex, antithrombin III, aprotinin, arga gotamine, ergonovine, ergotamine, ergotamine tartrate, and troban, bivalirudin, cilostazol, clopidogrel, coagulation methylergonovine. factor VIIa recombinant, dalteparin, danaparoid, dipy US 2008/0280955 A1 Nov. 13, 2008 ridamole, enoxaparin, eptifibatide, Factor VIIa, Factor VIII, calcitonin-Salmon, etidronate, gallium nitrate, pamidronate, Factor IX, fondaparinux, heparin Sodium, lepirudin, phytona plicamycin, risedronate, Sodium fluoride, teriparatide, tiludr dione K. protamine, reteplase, Streptokinase, tenecteplase, onate, Zoledronic acid. ticlopidine, tinzaparin, tirofiban, tranexamic acid, urokinase, 0225. Beta-lactam antibiotics and other inhibitors of cell warfarin. wall synthesis include the penicillins, such as amoxicillin, 0220 Hypothalamic and pituitary hormones include bro amoxicillin/potassium clavulanate, amplicillin, amplicillin/ mocriptine, cabergoline, cetrorelix, chorionic gonadotropin Sulbactam Sodium, carbenicillin, dicloxacillin, mezlocillin, hCG, corticorelinovine, corticotropin, cosyntropin, desmo nafcillin, oxacillin, penicillin G benzathine, penicillin G pressin, follitropin alfa, follitropen beta IFSH), ganirelix, procaine, penicillin V, piperacillin, pipercillin and taZobac gonadorelin acetate GnRH, gonadorelin hydrochloride tam Sodium, ticarcillin, and ticarcillin/clavulanate potassium; GnRH, goserelin acetate, histrelin, leuprolide, menotropins the cephalosporins and other beta-lactam drugs, such as the hMG, nafarelin, octreotide, oxytocin, pergolide, protirelin, narrow spectrum (first generation) cephalosporins, e.g., sermorelin, Somatrem, Somatropin, thyrotropin alpha, trip cefadroxil, cefazolin, cephalexin, cephalothin, cephapirin, torelin, urofollitropin, vasopressin. and cephradine; the second generation (intermediate spec 0221) Thyroid and antithyroid drugs include the thyroid trum) cephalosporins, e.g., cefaclor, cefamandole, cefimeta agents: levothyroxine T. liothyronine T. liotrix a 4:1 Zole, cefonicid, cefotetan, cefoxitin, cefprozil, cefuroxime, ratio of T.T., thyroid desiccated USP; and the antithyroid andloracarbef; the broad spectrum (third- and fourth-genera agents: diatrizoate Sodium, iodide, iopanoic acid, ipodate tion cephalosporins, e.g., cefdinir, cefditoren, cefepime, Sodium, methimazole, potassium iodide, propylthiouracil cefixime, cefoperaZone, cefotaxime, cefpodoxime proxetil, IPTU, thyrotropin; recombinant human TSH. ceftazidime, ceftibuten, ceftizoxime, and ceftriaxone. Further 0222 Adrenocorticosteroids and adrenocortical antago classes include the carbapenem and monobactam, e.g., aztre nists include the glucocorticoids for oral and parenteral use: onam, ertapenem, imipenen/cilastatin, and meropenem; and betamethasone, betamethasone sodium phosphate, cortisone, other drugs such as cycloserine (seromycin pulvules), fosfo dexamethasone, dexamethasone acetate, dexamethasone mycin, Vancomycin. Sodium phosphate, hydrocortisone cortisol, hydrocortisone 0226. Other antibiotics include chloramphenicol, the tet acetate, hydrocortisone cypionate, hydrocortisone sodium racyclines, e.g., demeclocycline, doxycycline, methacycline, phosphate, hydrocortisone sodium Succinate, methylpred minocycline, oxtetracycline, and tetracycline; the mac nisolone, methylprednisolone acetate, methylprednisolone rolides, e.g., azithromycin, clarithromycin, erythromycin; the Sodium Succinate, prednisolone, prednisolone acetate, pred ketolides, e.g., tellithromycin; the lincomycins, e.g., clinda nisolone sodium phosphate, prednisolone tebutate, pred mycin; the streptogramins, e.g., quinupristin and dalfopristin; nisone, triamcinolone, triamcinolone acetonide, triamcino and the oxazolidones, e.g., lineZolid. lone diacetate, triamcinolone hexacetonide. Another class of 0227 Aminoglycosides and spectinomycin antibiotics adrenocorticoids are the mineralocorticoids, e.g., fludrocor include amikacin, gentamicin, kanamycin, neomycin, tisone acetate. The adrenal steroid antagonists include ami netilmicin, paromomycin, spectinomycin, Streptomycin, and noglutethimide, ketoconazole, mitotane. tobramycin. 0223 Gonadal hormones and inhibitors include the estro 0228 Sulfonamides, trimethoprim, and quinolone antibi gens: conjugated estrogens, dienestrol, diethylstilbestrol otics include the general-purpose Sulfonamides, e.g., Sulfadi diphosphate, esterified estrogens, estradiol cypionate in oil, azine, Sulfamethizole, Sulfamethoxazole, Sulfanilamide, and estradiol, estradiol transdermal, estradiol Valerate in oil, Sulfisoxazole; the Sulfonamides for special applications, e.g., estrone aqueous Suspension, estropipate, ethinyl estradiol; mafenide, silver Sulfadiazine, Sulfacetamide sodium. Trime the progestins: hydroxyprogesterone caproate, levonorg thoprims include trimethoprim, trimethoprim-sulfamethox estrel, medroxyprogesterone acetate, megestrol acetate, nore azole co-trimoxazole, TMP-SMZ; the quinolones and fluo thindrone acetate, norgestrel, progesterone; the androgens roquinolones include cinoxacin, ciprofloxacin, enoxacin, and the anabolic Steroids: methyltestosterone, nandrolone gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin, nali decanoate, Oxandrolone, oxymetholone, Stanozolol, testolac dixic acid, norfloxacin, ofloxacin, sparfloxacin, and trova tone, testosterone aqueous, testosterone cypionate in oil, tes floxacin. tosterone enanthate in oil, testosterone propionate in oil, tes 0229 Antimycobacterial drugs include drugs used in tosterone transdermal system, testosterone pellets. Drugs tuberculosis, e.g., aminosalicylate sodium, capreomycin, may further be classed as antagonists and inhibitors of cycloserine, ethambutol, ethionamide, isoniazid, pyraZina gonadal hormones: anastroZole, bicalutamide, clomiphene, mide, rifabutin, rifampin, rifapentine, and streptomycin; and danazol, dutasteride, exemestane, finasteride, flutamide, full drugs used in leprosy, e.g., clofazimine, dapsone. Vestrant, letrozole mifepristone, nilutamide, raloxifene, 0230 Antifungal agents include amphotericin B, buta tamoxifen, and toremifene. conazole, butenafine, caspofungin, clotrimazole, econazole, 0224 Agents that affect bone mineral homeostasis include fluconazole, flucytosine, griseofulvin, itraconazole, keto Vitamin E, its metabolites and analogs: calcifediol, calcitriol, conazole, miconazole, naftifine, natamycin, nystatin, oxi cholecalciferol D, dihydrotachysterol DHT), doxercalcif conazole, Sulconazole, terbinafine, terconazole, tioconazole, erol, ergocalciferol D, and paricalcitol; calcium: calcium tolnaftate, and Voriconazole. acetate 25% calcium, calcium carbonate 40% calcium, 0231. Antiviral agents include abacavir, acyclovir, ade calcium chloride 27% calcium, calcium citrate 21% cal fovir, amantadine, amprenavir, cidofovir, delavirdine, cium, calcium glubionate 6.5% calcium; calcium glu didanosine, efavirenz, enfuVirtide, famciclovir, fomivirsen, ceptate 8% calcium, calcium gluconate 9% calcium, cal foscarnet, ganciclovir, idoxuridine, imiquimod, indinavir, cium lactate 13% calcium, and tricalcium phosphate 39% interferon alfa-2a, interferon alpha-2b, interferon-2b, inter calcium; phosphate and phosphate binders such as phos feron alfa-n3, interferon alfacon-1, lamivudine, lopinavir/ phate and sevelamer; and other drugs such as alendronate, ritonavir, nelfinavir, nevirapine, oseltamivir, palivizumab, US 2008/0280955 A1 Nov. 13, 2008 34 peginterferon alfa-2a, peginterferon alfa-2b, penciclovir, rib avirin, rimantadine, ritonavir, saquinavir, stavudine, teno TABLE 8-continued fovir, trifluridine, Valacyclovir, Valgancyclovir, Zalcitabine, Zanamivir, and Zidovudine. Structural Classes of Antibiotic Drugs 0232 Further antimicrobial agents, disinfectants, antisep Aminoglycosides Armastatin, Amikacin, Gentamicin, tics, and sterilants include the miscellaneous antimicrobial Hygromicin, Kanamycin, Streptomycin Benzochinoides Herbimycin agents, e.g., methenamine hippurate, methenamine mande Carbapenems mipenem, Meropenem late, metronidazole, mupirocin, nitrofurantoin, polymyxin B; Coumarin-glycosides Novobiocin and the disinfectants, antiseptics, and sterilants, e.g., benza Fatty Acid Derivatives Cerulenin Ikonium, benzoyl peroxide, chlorhexidine gluconate, glut Glucosamines -deoxynoirimycin Glycopeptides Bleomycin, Vancomycin araldehyde, hexachlorophene, iodine aqueous, iodine tinc Imidazoles Metroidazole ture, nitrofuraZone, oxychlorosene Sodium, providone Penicillins Benzylpenicillin, BenZathine penicillin, iodine, sliver nitrate, and thimerosal. Amoxycillin, Piperacillin Macrollides Amphotericin B, Azithromycin, Erythromycin 0233 Antiprotozoal drugs include albendazole, atova Nucleosides Cordycepin, Formycin A, Tubercidin quone, atovaquone-proguanil, chloroquine, clindamycin, Peptides Cyclosporin A, Echinomycin, Gramicidin doxycycline, dehydroemetine, eflornithine, halofantrine, Peptidyl Nucleosides Blasticidine, Nikkomycin iodoquinol, mefloquine, melarsoprol, metronidazole, nifur Phenicoles Chloramphenicol, Thiamphenicol timox, nitazoxanide, paromomycin, pentamidine, pri Polyethers LaSalocid A, Salinomycin Quinolones 8-quinolinol, Cinoxacin, Ofloxacin maquine, pyrimethamine, quinidine gluconate, quinine, Steroids Fusicic Acid Sodium Stibogluconate, Sulfadoxine and pyrimethamine, and Sulphonamides Sulfamethazine, Sulfadiazine, Trimethoprim Suramin. Tetracyclins Oxytetracyclin, Minocycline, Duramycin 0234 Anthelmintic drugs include albendazole, bithionol, diethylcarbamazine, ivermectin, levamisole, mebendazole, 0238. In some embodiments, drugs are classed as optical metrifonate, niclosamide, oxamniquine, oxantel pamoate, isomers, where a class is two or more optical isomers, or piperazine, praziquantel, pyrantel pamoate, Suramin, thia racemate, of a compound of the same chemical formula. bendazole. Thus, the invention includes methods and compositions for 0235 Immunopharmacological agents include abcix screening individuals for a genetic variation and/or pheno imab, adalimumab, alefacept, alemtuzumab, anti-thymocyte typic variation that predicts responsiveness to a first drug, and globulin, azathioprine, basiliximab, BCG, cyclophospha using this association to determine whether or not to modu mide, cyclosporine, daclizumab, etanercept, gemtuzumab, late the treatment of an individual with a second drug, where glatiramer, ibritumomab tiuxetan, immune globulin intrave the first and second drugs are optical isomers. In some nous, infliximab, interferon alfa-2a, interferon alfa 2b, inter embodiments, the first drug is a racemate and the second drug feron beta-1a, interferon beta-1b, interferon gamma-1b, inter is a stereoisomer that is a component of the racemate. In some leukin-2, IL-2, aldesleukin, leflunomide, levamisole, embodiments the first drug is a stereoisomer and the second lymphocyte immune globulin, methylprednisolone sodium drug is a racemate that includes the Stereoisomer. In some succinate, muromonab-CD3 OKT3, mycophenolate embodiments the first drug is a first stereoisomer and the mofetil, pegademase bovine, peginterferon alfa-2a, peginter second drug is a second stereoisomer of a compound. feron alfa-2b, prednisone, RH(D) immune globulin micro 0239. In some embodiments, drugs are classed as different dose, rituximab, sirolimus, tacrolimus FK506, thalidomide, crystal structures of the same formula. Thus, the invention and trastuzumab. includes methods and compositions for Screening individuals 0236 Heavy metal chelators include deferoxamine, for a genetic variation and/or phenotypic variation that pre dimercaprol, edetate calcium calcium EDTA, penicil dicts responsiveness to a first drug, and using this association lamine, Succimer, and unithiol. to determine whether or not to modulate the treatment of an b. Structural Classes of Drugs individual with a second drug, where the first and second 0237. In another example of drug classification embodi drugs are members of a class of drugs of the same chemical ments, a drug may be classified according to its structural formula but different crystal structures. class or family; certain drugs may fall into more than one 0240. In some embodiments, drugs are classed by struc structural class or family. Thus, in some embodiments, drugs tural components common to the members of the class. Thus, are classified according to structure. Drugs that have a com the invention includes methods and compositions for screen mon action may have different structures, and often one of the ing individuals for a genetic variation and/or phenotypic best predictors of a drugs likely action is its structure. By way variation that predicts responsiveness to a first drug, and using of example only, certain classes of drugs may be further this association to determine whether or not to modulate the organized by chemical structure classes presented herein. treatment of an individual with a second drug, where the first One non-limiting example is antibiotics. Table 8, below, pre and second drugs are members of a class of drugs that contain sents non-limiting examples of antibiotics further classified the same structural component. By way of example only, a by illustrative chemical structure classes. drug may be structurally classified as an acyclic ureide; acy lureide; aldehyde; amino acid analog; aminoalkyl ether TABLE 8 (clemastine, doxylamine); aminoglycoside; anthracycline; azalide; azole; barbituate; benzodiazapene; carbamate (e.g., Structural Classes of Antibiotic Drugs felbamate, meprobamate, emylcamate, phenprobamate); car Structure Class Examples of Antibiotics within Structure Class bapenam; carbohydrate; carboxamide (e.g., carbamazepine, Amino Acid Derivatives AZaserine, Bestatin, Cycloserine, oXcarbazepine); carotenoid (e.g., lutein, Zeaxanthin); cepha 6-diazo-5-oxo-L-norleucine losporin; cryptophycin; cyclodextrin; diphenylpropylamine; expanded porphyrin (e.g. rubyrins, Sapphyrins); fatty acid; US 2008/0280955 A1 Nov. 13, 2008 glycopeptide; higher alcohol; hydantoins (e.g., phenyloin): for a disorder for a genetic variation indicating a predisposi hydroxylated anthroquinone; lincosamide; lipid, lipid related tion to a response to first drug and administering or not admin compound; macrollide; mustard; nitrofuran; nitroimidazole; istering a second drug to the individual based on the results of non-natural nucleotide; non-natural nucleoside, oligonucle the screening. In some embodiments the first drug and the otide; organometallic compound; oxazolidinedione; penicil second drug are the same; in other embodiments they are lin; phenothiazine derivative (alimemazine, promethazine); different, e.g., different members of a class of drugs. Such phenylpiperidine, phthalocyanine; piperazine derivative screening can be used, for example, to identify individuals (e.g., cetrizine, meclozine); platinum complex (e.g., cis-pl atin); polyene; polyketide; polypeptide; porphyrin; prostag who may benefit (or not benefit) from treatment with a drug, landin (e.g., misoprostol, enprostil); purine; pyrazolone; pyri individuals who may be enrolled (or excluded) from a clinical midine; pyrrolidine (levetiracetam); quinolone; quinone; trial, and/or individuals who may suffer (or not suffer) an retinoid (e.g., isotretinoin, tretinoin); Salicylate: Sphin adverse reaction from a drug. In some embodiments one or golipid; steroid (e.g., prednisone, triamcinolone, hydrocorti more phenotypes may also be included in the screening step. sone); Substituted alkylamine (e.g., talastine, chlorphe 0244. In some embodiments, methods of the invention namine); Substituted ethylene diamine(mepyramine, include methods of Screening and treatment of an individual thonzylamine); Succinimide (ethoSuximide, phensuximide, Suffering from a disorder of blood glucose regulation, e.g., an meSuximide); Sulfa, Sulfonamide(sulfathiazole, mafenide); insulin resistance disorder, that include screening an indi Sulfone; taxane; tetracycline (e.g., chlortetracycline, oxytet vidual in need of treatment for a disorder of blood glucose racline); texaphyrin (e.g., Xcytrin, Antrin); thiazide; thiazo regulation, e.g., an insulin resistance disorder, for a genetic lidinedione; tocopherol, tocotrienol, triazine (e.g., lamot variation indicating a predisposition to a response to a first rigine); urea; Xanthine (theobromine, aminophylline); and insulin sensitizer, and administering or not administering a Zwitterion. second insulin sensitizer to the individual based on the results c. Implementation of the screening. In some embodiments, the first and second 0241 The present inventors have recognized that one or insulin sensitizers are the same. In some embodiments, the more genetic variations and/or phenotypes associated with a response to a first drug are useful in predicting probable first and second insulin sensitizers are different, e.g., different responses to a second drug in the same class, and, if necessary, members of a single class of drugs. Such screening can be in guiding possible modulations of the administration of the used, for example, to identify individuals who may benefit (or second drug. In some embodiments, the first and second not benefit) from treatment with an insulin sensitizer, indi drugs are the same drug; in some embodiments, the first and viduals who may be enrolled (or excluded) from a clinical second drugs are different drugs. Such predictions can be trial, and/or individuals who may suffer (or not suffer) an used in, e.g., clinical trials or in therapeutic practice to adverse reaction from an insulin sensitizer. In some embodi increase the probability that the second drug is administered ments one or more phenotypes may also be included in the to an appropriate patient population and/or is administered in Screening step. Such a way as to maximize the probability of a positive (e.g., 0245 Genetic variations, e.g., SNPs, used in the screening therapeutic) response and minimize the probability of a nega steps of the methods herein may be any genetic variations that tive (e.g., adverse) response. have been found to be associated with a type of responsive 0242 Implementing the methods and compositions of the ness to drug, e.g., an insulin sensitizer that is of interest, e.g., invention is a matter of routine use of information and tech Susceptibility to adverse effects of drug, e.g., an insulin sen niques that are well-known and well-established in the art. A sitizer. In some embodiments, one or more genetic variations number of databases of genetic variations, such as SNPs, are are SNPs found in the associations studies described herein. well-established, as described herein; indeed, a large number In some embodiments, one or more genetic variations are of human SNPs have been mapped and described. Methods of testing large numbers of genetic variations with rapidity and SNPs available on databases, and these SNPs are genotyped. accuracy are known and in routine use in the art. Response to 0246. Once a SNP or other genetic variation has been drugs are currently noted and cataloged for individuals identified, various compositions useful in Screening, diagno enrolled in research studies, such as clinical trials, and sis, prognosis, and the like, may be made. These include include therapeutic responses (as well as the degree of nucleic acids, polypeptides, antibodies, and the like. Such response) and non-therapeutic responses, e.g., adverse compositions and methods are described in detail in U.S. effects. Mechanistic and structural classes of drugs are application Ser. No. 10/447,685, filed May 28, 2003, entitled known, so that drugs in each class can be related to one “Liver Related Disease Compositions and Methods: U.S. another, numerous exemplary classifications are presented Provisional Patent Application No. 60/648,957, filed Jan. 31, herein. Sophisticated and powerful software for associating 2005, entitled “Compositions and Methods for Treating, Pre one factor with another (e.g. genetic variation with drug venting, and Diagnosing Alzheimer's Disease: U.S. Provi response) are available, as are the statistical methods neces sional Patent Application No. 60/653,672, filed Feb. 16, 2005, sary for Such software. Thus, the methods and compositions entitled “Parkinson's Disease-Related Disease Composition of the invention require no more than routine experimentation and Methods:” U.S. application Ser. No. 1 1/344.975, filed in their implementation. Jan. 31, 2006, entitled “Genetic Basis of Alzheimer's Disease and Diagnosis and Treatment Thereof.” U.S. application Ser. V. Screening and Treatment Methods and No. 1 1/299,298, filed Dec. 9, 2005, entitled “Markers for Compositions Metabolic Syndrome Obesity and Insulin Resistance: U.S. Provisional Patent Application No. 60/781,483, filed Mar. 10, 0243 Methods of the invention include methods of 2006, entitled “Markers for Breast Cancer: U.S. Provisional screening and treatment of an individual Suffering from a Patent Application No. 60/760,198, filed Jan. 19, 2006, disorder include screening an individual in need of treatment entitled “Markers for Myocardial Infarction;' and U.S. Pro US 2008/0280955 A1 Nov. 13, 2008 36 visional Patent Application No. 60/811,318, filed Jun. 6, from about 10kb upstream to about 10 kb downstream of the 2006, entitled “Markers for Addiction, all of which are incor nucleic acid. In some embodiments the region extends from porated herein by reference. about 5 kb upstream to about 5 kb downstream of the nucleic acid. In some embodiments the region extends from about 2 A. Nucleic Acids kb upstream to about 2 kb downstream of the nucleic acid. In 0247 The term “drug response nucleic acid.” “drug some embodiments the region extends from about 1 kb response associated genomic region, or 'associated genomic upstream to about 1 kb downstream of the nucleic acid. The region' means a nucleic acid, or fragment, derivative, variant invention also contemplates nucleic acids that are not within or complement thereof, associated with a response to a drug a gene that are nonetheless associated with a response to an (wherein, as used herein, “response' or “responsiveness” insulin sensitizer, and these nucleic acids are also encom includes the lack of an effect in the individual from the drug) passed by the term “insulin sensitizer response nucleic acid.” including, for example, coding and non-coding regions of an The term also includes nucleic acids similarly related to genes associated gene, and/or genomic regions spanning regions in an associated gene pathway. extending upstream and about downstream of the nucleic acid 0249. A drug response nucleic acid, e.g., an insulin sensi of an associated gene, and variants thereof. The term “asso tizer response nucleic acid, can include coding sequence and/ ciated gene' as used herein refers to a gene that is associated or non-coding sequence. It can comprise, consist essentially with a response to a drug. In some embodiments the associ of or consist of the exon or intron encompassing Such posi ated genomic region extends from about 10 kb upstream to tion. It can be of variable length. In some embodiments such about 10 kb downstream of the associated gene. In some a nucleic acid can be less than 500,000, 100,000, 50,000, embodiments the region extends from about 5 kb upstream to 10,000, 5,000, 1,000, 500, 100, 10 or 5 nucleotides in length. about 5 kb downstream of the associated gene. In some In some embodiments such a nucleic acid can be greater than embodiments the region extends from about 2 kb upstream to 5, 10, 50, 100, 300, 600, 900, 1,000, 3,000, 6,000, 9,000, about 2 kb downstream of the associated gene. In some 10,000, 30,000, 60,000, 90,000, 100,000, 300,000, 600,000, embodiments the region extends from about 1 kb upstream to or 900,000 nucleotides in length. about 1 kb downstream of the associated gene. In some 0250 In one embodiment, a drug response nucleic acid, embodiments, the associated genomic region includes regu e.g., an insulin sensitizer response nucleic acid, is one that can latory regions that modulate expression of an associated gene. specifically hybridize to an associated genomic region The invention also contemplates nucleic acids that are prod encompassing a nucleic acid position known to be a genetic ucts of an associated gene, e.g., RNA transcripts and splicing variation associated with response to the drug, e.g., insulin variants, modifications or derivatives thereof, etc. The inven sensitizer, e.g., a SNP, or an associated genomic region com tion also contemplates nucleic acids that are not within a gene prising a nucleic acid in a haplotype block with the position. that are nonetheless associated with a response to a drug, and Methods for identifying variants in a common haplotype these nucleic acids are also encompassed by the term “drug block are provided in U.S. Pat. No. 6,969,589, assigned to the response nucleic acid.” The nucleic acids of the invention same assignee as the present application. may contain one or more associated polymorphisms (e.g., 0251. The term “drug response polypeptide' refers to any SNPs). For example, the sequence of an associated gene in an peptide, polypeptide, or fragment, derivative or variant individual may contain one or more alleles associated with a thereof, associated with responsiveness to drug (wherein, as drug response, one or more alleles associates with a lack of used herein, “response' or “responsiveness” includes the lack response, or a combination thereof. The term also includes of an effect in the individual from the drug), including a nucleic acids similarly related to genes in an associated gene peptide or polypeptide regulated or encoded, in whole or in pathway. The term “associated gene pathway’ generally part, by an associated gene or genomic regions immediately refers to genes and gene products comprising a drug response upstream or downstream of an associated gene, or fragment, pathway, and may include one or more genes that act variants, derivative, or modifications thereof. The term also upstream or downstream of an associated gene in a drug includes such polypeptides up- or down-stream in an associ response pathway; or any gene whose gene product interacts ated gene pathway. with, binds to, competes with, induces, enhances or inhibits, 0252. The term “insulin sensitizer response polypeptide' directly or indirectly, the expression or activity of an associ refers to any peptide, polypeptide, or fragment, derivative or ated gene; or any gene whose expression or activity is variant thereof, associated with responsiveness to an insulin induced, enhanced or inhibited, directly or indirectly, by an sensitizer (wherein, as used herein, “response' or “respon associated gene; or any gene whose gene product is induced, siveness' includes the lack of an effect in the individual from enhanced or inhibited, directly or indirectly, by an associated the insulin sensitizer), including a peptide or polypeptide gene. An associated gene pathway may refer to one or more regulated or encoded, in whole or in part, by an associated genes. gene or genomic regions immediately upstream or down 0248. The term “insulin sensitizer response nucleic acid stream of an associated gene, or fragment, variants, deriva or “insulin sensitizer response associated genomic region' tive, or modifications thereof. The term also includes such means a nucleic acid, or fragment, derivative, variant or polypeptides up- or down-stream in an associated gene path complement thereof, associated with a response to an insulin way. sensitizer (wherein, as used herein, “response' or “respon 0253) The term “stringent conditions' refers to conditions siveness' includes the lack of an effect in the individual from for hybridization of complementary nucleic acid wherein the the insulin sensitizer) including, for example, coding and presence of a nucleic acid may be detected. Different strin non-coding regions of an associated gene, and/or genomic gency conditions may be utilized under different circum regions spanning regions extending upstream and about stances. Stringent conditions depend on, for example, length downstream of the nucleic acid of an associated gene, and of the nucleic acids, temperature and buffers. Generally, strin variants thereof. In some embodiments the region extends gent conditions are selected to be about 5° C. lower than the US 2008/0280955 A1 Nov. 13, 2008 37 thermal melting point (Tm) of a specific sequence at a defined acid associated with response to drug, e.g., an insulin sensi ionic strength and pH. The Tm is the temperature (under tizer is one that is expressed differently in individuals having defined ionic strength, pH and nucleic acid concentration) at a phenotype of response to the drug as compared to individu which 50% of the complementary nucleic acids hybridize to als not having the same phenotype of response to the drug, or a target nucleic acid at equilibrium. As target nucleic acids are a nucleic acid having one or more variants associated with generally present in excess, at Tm, 50% of the complemen response to the drug. tary nucleic acids are occupied at equilibrium. Typically, (0258 Tables 9-11 identify SNPs from the analysis of indi stringent conditions include a salt concentration of at least vidual genotypes that have significant association with drug about 0.01 to 1.0 MNaion concentration (or other salts) at pH response (nominal p-value <0.001), e.g., edema. Table 9 pro 7.0 to 8.3 and the temperature is at least about 30°C. for short vides a collection of 345 variant sites having forms associated probes (e.g., 10 to 50 nucleotides). Stringent conditions can with Susceptibility or resistance to drug response, e.g., edema. also be achieved with the addition of destabilizing agents Further information about the variant sites provided in Table such as formamide. For example, conditions of 5xSSPE (750 9 is shown in Tables 10 and 11. The variant sites occur in or mMNaCl, 50 mMNaPhosphate, 5 mM EDTA, pH 7.4) and a proximal to the genes provided in Table 10. Further informa temperature of 25-30° C. are suitable for allele-specific tion about the variant sites, their alleles, and the statistical nucleic acid hybridizations. In certain embodiments, sample analysis identifying them as associated with drug response, nucleic acid comprises target nucleic acid and complemen e.g. edema, is provided in Table 11. tary nucleic acids are immobilized on a Substrate. 0259 Table 9, column 1, entitled “rsID, lists a SNP iden 0254 The terms “isolated” and “purified” refer to a mate tification number from dbSNP (NCBI) for each variant. The rial that is substantially or essentially removed from or con NCBI dbSNP database is publicly accessible (ncbi.nlm.nih. centrated in its natural environment. For example, an isolated gov/projects/SNP?). nucleic acid may be one that is separated from the nucleic 0260 Table 9, column 2, entitled “ssID, contains a sub acids that normally flank it or other nucleic acids or compo mission identifier for Applicants’ submission to dbSNP. nents (proteins, lipids, etc.) in a sample. In another example, 0261 Table 9, column 3, entitled “Chridentifies the chro a polypeptide is purified if it is substantially removed from or mosome on which the variant is mapped. concentrated in its natural environment. Methods for purifi 0262 Table 9, column 4, entitled 'Accession', identifies cation and isolation of nucleic acids are well known in the art. the accession number for the contig containing each variant 0255. The term “nucleic acid.” refers to a deoxyribonucle according to NCBI Build 35 of the human genome. otide, ribonucleotide and/or a mimetic thereof, whether sin 0263 Table 9, column 5, entitled “Position, identifies the gular or in polymers, naturally occurring or non-naturally position of each variant in the contig identified in column 4. occurring, double-stranded or single-stranded, translated 0264. Table 9, column 6, entitled “Assayed Sequence', is (e.g., gene) or untranslated (e.g. regulatory region), or any a nucleotide sequence encompassing the variant that may be fragments, derivatives or complements thereof. A nucleic used to identify the variant in a sample, e.g., by hybridization. acid includes analogs (e.g., phosphorothioates, phosphorami For example, the assayed sequence may be tiled on an array dates, methyl phosphonate, chiral-methyl phosphonates, for hybridization to and thereby identification of the variant. 2-O-methyl ribonucleotides) or modified nucleic acids (e.g., 0265 Additional variants (and their associated gene modified backbone residues or linkages) or nucleic acids that regions) that can be used to determine an appropriate drug are combined with carbohydrate, lipids, protein or other treatment regimen for an individual include, but are not lim materials or peptide nucleic acids (PNAS). A nucleic acid can ited to, those in haplotype blocks with the variants identified include one or more polymorphisms, variations or mutations. in Table 9. Such variants can be identified according to U.S. Examples of nucleic acids include oligonucleotides, nucle Pat. No. 6,969.589, assigned to the same assignee as the otides, polynucleotides, nucleic acid sequences, genomic present application. A variant in a haplotype block with a sequences, antisense nucleic acids, probes, primers, genes, variant of Table 9 that is associated with a drug response (e.g., regulatory regions, introns, exons, open-reading frames, edema) is also associated with the drug response. More spe binding agents, target nucleic acids and allele specific nucleic cifically, a variant allele in a haplotype pattern with a variant acids. allele of Table 1 that is associated with a drug response (e.g., 0256 The terms “polypeptide,” “peptide,” “oligopeptide' edema or lack thereof) is also associated with a drug response. and “protein’ are used interchangeably to refer to a polymer 0266 Table 10 lists the genetic variants of Table 9 by rsID of amino acids, PNAS or mimetics, of no specific length and and SSID, the name of the gene within 10 kb of the variant, as to all fragments, isoforms, variants, derivatives and modifi well as the location of the variant with respect to the gene, as cations thereof. A polypeptide may be naturally and non follows: “up' indicates that the variant is located upstream of naturally occurring. The term isoform refers to different gene the coding region of the gene; "down indicates that the products resulting from the same gene, e.g., due to alternative variant is located downstream of the coding region of the splicing. The term variant when used to describe a polypep gene: “intron’ indicates that the variant is located within an tide refers to variations in amino acid sequences, whether or intron of the gene: “nonsyn indicates that the variant is not such variations result in conservative or non-conservative located in the coding region of the gene and is a non-synony Substitutions. The term modification include tags, labels, mous polymorphism; and “syn' indicates that the variant is post-translational modifications or other chemical or biologi located in the coding region of the gene and is a synonymous cal modifications. In one embodiment a polypeptide is puri polymorphism. The genes in Table 10 correspond to an old fied. annotation of the genome, so the SNP-gene mappings may 0257 "Response to a drug. e.g., “Response to an insulin change slightly as the annotations are updated in this region. sensitizer” or "drug response, e.g., “insulin sensitizer For example, additional genes may be mapped to this region. response' is as described herein, and includes therapeutic and However, the ssIDs, rsIDs and accession number-based posi non-therapeutic responses (e.g., adverse effects). A nucleic tions are typically stable in terms of defining the SNP posi US 2008/0280955 A1 Nov. 13, 2008

tions. As such, even though the nucleotide positions may 6 variants, at least 7 variants, at least 8 variants, at least 9 change, the SNP positions provided here will still be identi variants, at least 10 variants, at least 15 variants, at least 20 fiable to one of ordinary skill in the art by, e.g., their rsID variants, at least 25 variants, at least 30 variants, at least 35 and/or ssID numbers. variants, at least 40 variants, at least 45 variants, at least 50 0267 Table 11 lists the genetic variants of Table 9 by rsID variants, at least 60 variants, at least 70 variants, at least 80 and ssID, their alleles (Allele 1 and Allele 2), the relative variants, at least 90 variants, or at least 100 variants associated allele frequency of Allele 1 in the cases and controls, and the with a response to drug, e.g., an insulin sensitizer or variants odds ratios and p values computed using logistic regression. in common haplotype blocks thereof. These statistics indicate that the variant is associated with 0271. A nucleic acid can be single-stranded or double drug response (e.g., edema). Specifically, the heterozygous Stranded. It can also be coding (e.g., exon) or non-coding odds ratio is defined as the odds of edema in persons with one sequence (e.g., introns, exon outside coding region, and 3' or copy of the predisposing allele (“associated allele') divided 5' untranslated regions) or a combination of coding and non by the odds of edema in persons with no copies of the predis coding nucleic acids. In one embodiment, a coding drug posing allele. For rare traits, the heterozygous odds ratio is nucleic acid, e.g., insulin sensitizer response nucleic acid, is closely related to the heterozygous relative risk, which is the one that can specifically hybridize to the complete coding ratio of the risk of presenting the trait in persons with one region of an associated genomic region, or to one or more copy of the predisposing allele to the risk in persons with no exons of an associated genomic region, or to one or more open copies of the predisposing allele. Logistic regression is a tool reading frames of an associated genomic region, or the for association analysis from which odds ratios were esti complementary sequence thereof. mated, under a multiplicative model of genetic risk; an analy 0272. A nucleic acid provided herein can be fused to sis of deviance of the edema trait, adjusting for principal another molecule. Such as a tag sequence, a reporter gene or a components that represent population structure and experi fusion protein. A sequence tag encodes a polypeptide that can mental variability, was used to estimate the significance of the assist in isolation or purification of the protein product (e.g., association. The p-value is the likelihood that the deviance glutathione-S-transferase (GST) fusion protein or a hemag attributable to SNP genotypes would be as extreme as the glutinin A (HA) polypeptide). A reporter gene encodes an observed deviance in the absence of a true association easily assayed protein and is often used to replace other between the genotype and edema. If the relative allele fre coding regions whose protein products are difficult to assay. A quency of Allele 1 is greater in the cases than the controls, fusion protein is formed by the expression of a hybrid nucleic then Allele 1 is associated with a given drug response (e.g., acid made by combining two coding nucleic acid sequences. edema) and Allele 2 is associated with the lack of that drug 0273 Conditions for nucleic acid hybridization vary response. If the relative allele frequency of Allele 1 is greater depending on the buffers used, length of nucleic acids, ionic in the controls than in the cases, then Allele 1 is associated strength, temperature, etc. The term "stringency conditions' with the lack of a given drug response (e.g., edema) and Allele for hybridization refers to the incubation and wash conditions 2 is associated with the presence or Susceptibility to the drug (e.g., conditions oftemperature and buffer concentration) that response. permit hybridization of a first nucleic acid to a second nucleic 0268 Table 12 provides a set of six SNPs that form a acid. The first nucleic acid may be perfectly (e.g. 100%) haplotype block found to be associated with drug response complementary to the second or may share some degree of (e.g., edema). This haplotype block is found on chromosome complementarity, which is less than perfect (e.g., more than 14 (genes: SERPINA10 and SERPINA6); three of the 6SNPs 70%, 75%, 85%, or 95%). For example, certain high strin in the associated haplotype are nonsynonymous SNPs in gency conditions can be used which distinguish perfectly SERPINA10. Table 12 lists the six SNPs, their rsIDs, and complementary nucleic acids from those less complemen their locations in the genome with respect to the SERPINA10 tary. High Stringency, moderate Stringency and low strin and SERPINA 6 genes. gency conditions for nucleic acid hybridization are known in the art. Ausubel, F. M. et al., "Current Protocols in Molecular TABLE 12 Biology” (John Wiley & Sons 1998), pages 2.10.1-2.10.16; 6.3.1-6.3.6. The exact conditions which determine the strin Associated Haplotype gency of hybridization depend not only on ionic strength SNP Index rSID Location (e.g., 0.2xSSC, 0.1 xSSC), temperature (e.g., room tempera 1 2232700 SERPINA10 non-synonymous ture, 42°C., 68°C.) and the concentration of destabilizing 2 941591 SERPINA10 non-synonymous agents such as formamide or denaturing agents such as SDS, 3 941590 SERPINA10 non-synonymous but also on factors such as the length of the nucleic acid 4 382,7896 SERPINA65', SERPINA103 sequence, base composition, percent mismatch between 5 8O15929 SERPINA65', SERPINA103 hybridizing sequences and the frequency of occurrence of 6 9416O1 SERPINA6 intron Subsets of that sequence within other non-identical sequences. Thus, equivalent conditions can be determined by 0269. The variants, polymorphisms, alleles and associated varying one or more of these parameters while maintaining a genomic regions identified herein can be used to identify, similar degree of identity or similarity between the two isolate and amplify nucleic acids associated with drug nucleic acid molecules. Typically, conditions are used Such response (e.g., edema). Such nucleic acids can be used for that sequences at least about 60%, at least about 70%, at least prognostics, diagnostics, theranostics and further study of the about 80%, at least about 90% or at least about 95% or more drug response. identical to each other remain hybridized to one another. By 0270. In some embodiments, a set of nucleic acids is pro varying hybridization conditions from a level of stringency at vided that can specifically hybridize to at least 2 variants, or at which no hybridization occurs to a level at which hybridiza least 3 variants, at least 4 variants, at least 5 variants, at least tion is first observed, conditions which will allow a given US 2008/0280955 A1 Nov. 13, 2008 39 sequence to hybridize (e.g., selectively) with the most similar 10/236,480, filed on Sep. 5, 2002, entitled “Methods for sequences in the sample can be determined. Exemplary con Amplification of Nucleic Acids”; and U.S. application Ser. ditions are described in Krause, et al., Methods in Enzymol No. 10/341,832, filed on Jan. 14, 2003, entitled “Apparatus ogy, (1991) 200:546-556 and in Ausubel, et al., “Current and Methods for Selecting PCR Primers Pairs (Short Range Protocols in Molecular Biology”, (John Wiley & Sons 1998), PCR Primer Picking), the disclosures of which are incorpo which describes the determination of washing conditions for rated herein in their entirety. moderate or low stringency conditions. Washing is the step in 0275. In some embodiments, the nucleic acids used in the which conditions are usually set so as to determine a mini invention are purified. There are various degrees of purity. mum level of complementarity of the hybrids. Generally, While a nucleic acid can be purified to homogeneity, prepa starting from the lowest temperature at which only homolo rations in which a nucleic acid is not purified to homogeneity gous hybridization occurs, each C. by which the final wash are also useful where the nucleic acid retains a desired func temperature is reduced (holding SSC concentration constant) tion even in the presence of considerable amount of other allows an increase by 1% in the maximum extent of mis components. In some embodiments, nucleic acids are Sub matching among the sequences that hybridize. Generally, stantially free of cellular material which includes prepara doubling the concentration of SSC results in an increase in tions of a nucleic acid having less than about 30% (dry TM of ~17°C. Using these guidelines, the washing tempera weight) other nucleic acids (e.g., contaminating nucleic ture can be determined empirically for high, moderate or low acids), less than about 20% other nucleic acids, less than stringency, depending on the level of mismatch sought. For about 10% other nucleic acids, or less than about 5% other example, a low stringency wash can comprise washing in a nucleic acids. solution containing 0.2xSSC/0.1% SDS for 10 min at room 0276 Nucleic acids that are substantially free of chemical temperature; a moderate stringency wash can comprise wash precursors or other chemicals generally include those that are ing in a prewarmed solution (42°C.) Solution containing separated from chemicals that are involved in its synthesis. In 0.2xSSC/0.1% SDS for 15 min at 42° C.; and a high strin one embodiment, the nucleic acids are substantially free of gency wash can comprise washing in prewarmed (68° C.) chemical precursors or other chemicals such that a prepara solution containing 0.1xSSC/0.1% SDS for 15 min at 68° C. tion of the nucleic acid has less than about 30% (dry weight) Furthermore, washes can be performed repeatedly or sequen chemical precursors or other chemicals, or less than about tially to obtain a desired result as known in the art. Equivalent 20% chemical precursors or other chemicals, or less than conditions can be determined by varying one or more of the about 10% chemical precursors or other chemicals or than parameters given as an example, as known in the art, while about 5% chemical precursors or other chemicals. maintaining a similar degree of identity or similarity between the target nucleic acid and the primer or probe used. Specific Probes and Primers examples of hybridization conditions and procedures pro 0277. The nucleic acids herein can be used as probes and vided in U.S. Provisional Patent Application No. 60/648,957, primers in various assays. The terms “probe(s) and “primer filed Jan. 31, 2005, entitled “Compositions and Methods for (s) refer to nucleic acids that hybridize, in whole or in part, Treating, Preventing, and Diagnosing Alzheimer's Disease: in a base specific manner to a complementary strand. Probes U.S. Provisional Patent Application No. 60/653,672, filed and primers include peptide nucleic acids, such as those Feb. 16, 2005, entitled “Parkinson's Disease-Related Disease described in Nielsen et al. (1991) Science 254:1497-1500. Composition and Methods: U.S. Provisional Patent Appli 0278 Typically, the term “primer' refers to a single cation No. 60/643,006, filed Jan. 11, 2005, entitled “Markers Stranded nucleic acid that can act as a point of initiation of for Metabolic Syndrome Obesity and Insulin Resistance: template directed DNA synthesis, such as PCR. In addition to U.S. application Ser. No. 10/284.444, filed Oct. 31, 2005, PCR, other suitable isolation, and amplification methods entitled “Human Genomic Polymorphism: U.S. application include, for example, the ligase chain reaction (LCR) (see Wu Ser. No. 10/447,685, filed May 28, 2003, entitled “Liver and Wallace, Genomics, 4:560 (1989), Landegren et al., Sci Related Disease Compositions and Methods; and U.S. ence, 241:1077 (1988), transcription amplification (Kwoh et Application Ser. No. unknown, docket no. 300/1081-10, al., Proc. Natl. Acad. Sci. USA, 86:1173 (1989)), self-sus filed Sep. 27, 2006, entitled “Genetic Basis of Rheumatoid tained sequence replication (Guatelli et al., Proc. Natl. Acad. Arthritis and Diagnosis and Treatment Thereof.” Sci. USA, 87: 1874 (1990)) and nucleic acid based sequence 0274. In some embodiments, the nucleic acids herein are amplification (NASBA). The latter two amplification meth perfectly complementary to identified genomic regions. In ods involve isothermal reactions based on isothermal tran Some embodiments, the nucleic acids herein comprise the scription that produces both single stranded RNA (ssRNA) genomic regions identified herein. Furthermore, a nucleic and double stranded DNA (dsDNA) as the amplified products acid can be isolated and/or purified, as described above. in a ratio of approximately 30-100 fold more ssRNA than Nucleic acids can be isolated and amplified using polymerase dsDNA. See, e.g., U.S. patent application Ser. No. 11/058, chain reaction (PCR) techniques known in the art. See Erlich, 432, filed Feb. 14, 2005, entitled “Selection Probe Amplifi H. A., “PCR Technology: Principles and Applications for cation, the disclosure of which is incorporated herein in its DNA Amplification” (ed. Freeman Press, NY, N.Y., 1992); entirety. Innis M.A., et al., “PCR Protocols: A Guide to Methods and 0279 PCR reactions can be designed based on the human Applications” (Eds. Academic Press, San Diego, Calif., genome sequence and the associated genomic regions or vari 1990); U.S. application Ser. No. 10/174,101, filed on Jun. 17, ants. For example, where a variant is located in an exon, Such 2002, entitled “Methods for Storage of Reaction Cocktails: exon can be isolated and amplified using primers that are U.S. Pat. No. 6,898,531, issued on May 24, 2005, entitled complementary to the nucleotide sequences at both ends of “Algorithms for Selection of Primers Pairs”; U.S. Pat. No. the exon. Similarly, where a variant is located in an intron, the 6,740,510, filed on Jan. 2, 2002, entitled “Methods for Ampli entire intron can be isolated and amplified using primers that fication of Nucleic Acids, U.S. Application Serial No. are complementary to the nucleotide sequences at both ends US 2008/0280955 A1 Nov. 13, 2008 40 of the intron. See, e.g., U.S. Pat. No. 6,898,531, issued on cDNA can be made either from selected tissues (e.g., normal May 24, 2005, entitled “Algorithms for Selection of Primers or diseased tissue), or from tissues of a mammal treated with, Pairs:"U.S. application Ser. No. 10/341,832, filed on Jan. 14, for example, a pharmaceutical agent. Alternatively, many 2003, entitled “Apparatus and Methods for Selecting PCR cDNA libraries are available commercially. In one embodi Primers Pairs;” and U.S. application Ser. No. 10/236,480, ment, members of the cDNA library are larger than a nucleic filed Sep. 5, 2002, entitled “Methods for Amplification of acid hybridization probe, and can contain the whole cDNA Nucleic Acids, the disclosures of which are incorporated native sequence. herein in their entirety. 0285 Genomic DNA can be isolated in a manner similar 0280. In some embodiments, a probe or a primer contains to the isolation of full-length cDNA. Briefly, the nucleic acids a region of at least about 10 contiguous nucleotides, or about herein, or fragments, derivatives or complement thereof, can 15 contiguous nucleotides, or about 20 contiguous nucle be used to probe a library of genomic DNA. Such libraries can otides, or about 30 contiguous nucleotides, or about 50 con be in vectors suitable for carrying large segments of a tiguous nucleotides, or between about 10 and about 50, or genome, such as P1 or YAC, as described in detail in Sam between about 10 and about 40, or between about 10 and brook et al., 9.4-9.30. In addition, genomic sequences can be about 30 contiguous nucleotides that can specifically hybrid isolated from human BAC libraries, which are commercially ize to a complementary nucleic acid sequence (e.g., a drug available from Research Genetics, Inc., Huntsville, Ala., response nucleic acid such as an insulin sensitizer response USA, for example. As an alternative, full-length cDNA, nucleic acid). In addition, in Some embodiments a primer is genomic DNA, or any nucleic acid, fragment, derivative or between about 10 and about 100, or between about 10 and complement thereof, can be obtained by synthesis. about 50, or between about 15 and about 35, or between about 16 and about 24, or between about 18 and about 22, or B. Polypeptides between about 26 and about 34, or between about 28 and 0286 The invention further provides polypeptides useful about 32, or about 18, 19, 20, 21, or 22 nucleotides in length, in Screening, diagnostics, prognostics, prevention, treatment, or about 28, 29, 30, 31, or 32 nucleotides in length. In some or study of responses to the drugs described herein, e.g., to an embodiments, a probe is between about 10 and about 60, or insulin sensitizer. Polypeptides of the invention include those between about 10 and about 50, or between about 15 and encoded by or regulated by associated genomic regions com about 35, or between about 20 and about 30, or about 22, 23, prising the variants of nucleic acids of the invention. The 24, 25, 26, 27, or 28 nucleotides in length. polypeptides, e.g., insulin sensitizer response polypeptides (0281. In order to isolate, amplify, and/or detect the pres herein may be naturally occurring or recombinantly produced ence of a nucleic acid associated with a response to drug, e.g., using methods known in the art. an insulin sensitizer, a probe or primer or set of such probes or 0287. A polypeptide of the invention, e.g., a polypeptide primers may include at least 1 variant, or at least 2 variants, or associated with a response to a drug such as an insulin sensi at least 3 variants, or at least 4 variants associated with a tizer may be one that is expressed differently in individuals response to an insulin sensitizer or variants in common hap having a phenotype of a response, e.g., a response to a drug lotype blocks with such variants. Such as an insulin sensitizer, as compared to individuals not 0282. In one embodiment, a probe or primer is at least having the same phenotype of response, or one that is regu about 70% identical, or at least about 80% identical, or at least lated or encoded in whole or in part by a nucleic acid associ about 90% identical, or at least about 95% identical, or about ated with a drug response, e.g., a response to an insulin 100% identical to a contiguous drug response nucleic acid, sensitizer. In one example, a polypeptide associated with a e.g., insulin sensitizer response nucleic acid comprising at drug response, e.g., a response to an insulin sensitizer can be least one drug response, e.g., insulin sensitizer response, recombinantly produced using an expression vector having a associated variant. In other embodiments a probe or a primer non-coding regulatory region associated with a drug is complementary to a nucleotide sequence that is at least 70% response, e.g., a response to an insulin sensitizer, operably identical, or at least about 80% identical, or at least about 90% linked to an associated genomic region coding sequence, e.g., identical, or at least about 95% identical, or about 100% a drug response gene Such as an insulin sensitizer response identical to a contiguous drug, e.g., insulin sensitizer, gene, in an expression vector. The expression vector is intro response nucleic acid comprising at least one insulin sensi duced into a host cellunderconditions appropriate for expres tizer response-associated variant. sion. The polypeptide can then be isolated from the host cell 0283. In any embodiment, a probe or primer may be using standard protein purification techniques. labeled (e.g., radioisotope, fluorescent compound, enzyme, 0288. In one embodiment, a polypeptide associated with a or enzyme co-factor). The probes and primers herein can be drug response, e.g., a response to an insulin sensitizer can be optionally labeled with, for example, a radioactive, fluores produced by inserting a vector comprising a coding nucleic cent, biotinylated or chemiluminescent label. Labeled nucleic acid associated with a drug response, e.g., a response to an acids are useful for detection of a hybridization complex and insulin sensitizer and then purifying the polypeptide can be used as probes for diagnostic and screening assays. expressed by the host cell. 0284 Labeled probes can be used in cloning of full-length 0289. In some embodiments, the polypeptides are puri cDNA or genomic DNA by screening cDNA or genomic fied. There are various degrees of purity. While a polypeptide libraries. Classical methods of constructing cDNA libraries can be purified to homogeneity, preparations in which a are taught in Sambrook et al., Supra. These methods provide polypeptide is not purified to homogeneity are also useful for the production of cDNA from mRNA and the insertion of where the polypeptide retains a desired function even in the the cDNA into viral or other expression vectors. Typically, presence of considerable amount of other components. In libraries of mRNA comprising poly(A)tails can be produced Some embodiments, polypeptides are Substantially free of with poly(T) primers. Similarly, cDNA libraries can be pro cellular material which includes preparations of a polypep duced using the nucleic acid herein as primers. Libraries of tide having less than about 30% (dry weight) other polypep US 2008/0280955 A1 Nov. 13, 2008 tides (e.g., contaminating polypeptides), less than about 20% stantial portion of a first polypeptide linked at the N- or other polypeptides, less than about 10% other polypeptides, C-terminus to all or a portion of a second polypeptide. For or less than about 5% other polypeptides. example, fusion proteins of the invention include a drug 0290 When a polypeptide is recombinantly produced, it response polypeptide, e.g., an insulin sensitizer response can also be substantially free of culture medium. In some polypeptide (a polypeptide associated with a response to embodiments, culture medium represents less than about drug, e.g., an insulin sensitizer) operatively linked to a non 20% of the volume of the polypeptidepreparation, or less than drug-response polypeptide, e.g., non-insulin sensitizer about 10% of the volume of the polypeptide preparation or response polypeptide or a heterologous polypeptide having less than about 5% of the volume of the polypeptide prepa an amino acid sequence not substantially homologous to a ration. Polypeptides that are substantially free of chemical precursors or other chemicals generally include those that are drug response amino acid sequence, e.g., an insulin sensitizer separated from chemicals that are involved in its synthesis. In response amino acid sequence. A further example is a first one embodiment, the polypeptides are substantially free of drug response polypeptide, e.g., a first insulin sensitizer chemical precursors or other chemicals such that a prepara response polypeptide (a polypeptide associated with a tion of the polypeptides has less than about 30% (dry weight) response to an insulin sensitizer) operatively linked to a sec chemical precursors or other chemicals, or less than about ond drug response polypeptide, e.g., a second insulin sensi 20% chemical precursors or other chemicals, or less than tizer response polypeptide. “Operatively linked' indicates about 10% chemical precursors or other chemicals or than that the polypeptide and the heterologous protein are fused, about 5% chemical precursors or other chemicals. for example, the non-insulin sensitizer response polypeptide 0291. As used herein, two polypeptides are substantially can be fused to the N-terminus or C-terminus of the insulin homologous when their amino acid sequences are at least sensitizer response polypeptide. In one embodiment, the about 45% homologous, or at least about 75% homologous, fusion polypeptide does not affect the function of drug or at least about 85% homologous, or greater than about 95% response polypeptide, e.g., the insulin sensitizer response homologous. To determine the percent homology of two polypeptide. Examples of fusion polypeptide that do not polypeptides, the amino acid sequences are aligned for opti affect the function of a polypeptide include a GST-fusion mal comparison purposes. The amino acid residues at corre polypeptides in which the drug response polypeptide, e.g., sponding positions are compared. The percent homology insulin sensitizer response polypeptide sequences arefused to between two amino acid sequences is a function of the num the C-terminus of the GST sequences. Other types of fusion ber of identical positions shared by the sequences (e.g. per polypeptides include enzymatic fusion polypeptides, for cent homology equals the number of identical positions/total example 3-galactosidase fusions, yeast two-hybrid GAL number of positions times 100). 0292 Some polypeptides (e.g., conservative variants) fusions, poly-His fusions and Ig fusions. Fusion polypep may have a lower degree of sequence homology but are still tides, especially poly-His fusions, can facilitate the purifica able to perform one or more of the same functions. Conser tion of recombinant polypeptide. In some host cells. Such as Vative Substitutions that can maintain the same function mammaliancells, expression and Secretion of a drug response include replacements among aliphatic amino acids methion polypeptide, e.g., an insulin sensitizer response polypeptide ine, Valine, leucine and isoleucine; interchange of the can be increased using a heterologous signal sequence. hydroxyl residues serine and threonine; exchange of acidic Therefore, in one embodiment, a drug response polypeptide, residues aspartic and glutamic acids; Substitution between e.g., an insulin sensitizer response polypeptide may be fused amide residues asparagine and glutamine, exchange between to a heterologous signal sequence at its N-terminus. In basic residues lysine and arginine, and replacements among another embodiment, a fusion protein may comprise of a drug aromatic residues phenylalanine, tyrosine and tryptophan. response polypeptide, e.g., an insulin sensitizer response Alanine and glycine may also result in conservative Substitu polypeptide and various portions of immunoglobulin con tions. stant regions such as the Fc portion. Fc portions are useful in 0293. Other polypeptides that may not be able to perform therapy and diagnosis and may result in improved pharmaco one or more of the same functions may be variants containing kinetic properties. Fc portions can also be used in high one or more non-conservative amino acid Substitutions or throughput Screening assays to identify binding molecules, deletions, insertions, inversions or Substitution of one or more agonists and antagonists. See, e.g., Bennett et al.; J. of Molec. amino acid residues. Amino acids that are essential for func Recog., (1995) 8:52-58 and Johanson et al., (1995).J. of Biol. tion of a polypeptide can be identified by various methods Chem., 270, 16:9459-9471. In one embodiment, soluble known in the art, Such as site-directed mutagenesis oralanine fusion proteins comprise of a drug response polypeptide, e.g., scanning mutagenesis. See Cunningham et al., (1989) Sci an insulin sensitizer response polypeptide and one or more of ence, 244: 1081-1085. The latter procedure can introduce a the constant regions of heavy or light chains of immunoglo single alanine mutation at every residue in the molecule. The bulins (e.g. IgG, IgM, IgA, Ig), IgE). resulting variants are then tested for biological activity in 0295) A fusion protein can be produced by standard vitro or in vivo. Residues that are critical for polypeptide recombinant DNA techniques as described herein. For activity or inactivity are identified by comparing the two example, DNA fragments coding for the different polypep variants (with and without the alanine mutation). Polypeptide tide sequences are ligated together in accordance with con activity can also be determined by structural analysis Such as ventional techniques. The fusion gene can be synthesized by crystallization, nuclear magnetic resonance or photoaffinity conventional techniques such as automated DNA synthesiz labeling. See Smith et al., (1992) J. Mol. Biol., 224:899-904; ers. Alternatively, PCR amplification of nucleic acid frag ments can be carried out using anchor primers which give rise and de Vos et al. (1992) Science, 255:306–312. to complementary overhangs between two consecutive Fusion Proteins nucleic acid fragments that can Subsequently be annealed and reamplified to generate a chimeric nucleic acid sequence. 0294 Any polypeptides herein can be made part of a Moreover, many expression vectors are commercially avail fusion protein. The term “fusion protein' or “fusion polypep able that already encode a fusion moiety (e.g., a GST protein). tide' as used herein refers to a protein that has all or a sub A nucleic acid encoding a polypeptide herein can be cloned US 2008/0280955 A1 Nov. 13, 2008 42 into Such an expression vector Such that the fusion moiety is herein. Identified members are then isolated using techniques linked in-frame to the polypeptide. known in the art. Kits for generating and Screening phage display libraries are commercially available. See for example, C. Antibodies the Pharmacia Recombinant Phage Antibody System, Cata 0296 Any of the polypeptides herein, or fragments, log No. 27-94.00-01, and the Stratagene SurjZAPTM Phage derivatives, or complements thereof, can be used as an immu Display Kit, Catalog No. 240612. Other methods and nogen (e.g. epitope) to generate polypeptide-specific antibod reagents for generating and screening antibody display librar ies. Antibodies can be used to detect, isolate and inhibit the ies are disclosed in PCT Publication No. WO92/01047: PCT activity of one or more polypeptides of the invention, e.g., Publication No. WO 90/028.09: Fuchs et al. (1991) Bio/Tech drug response polypeptides such as insulin sensitizer nology, 9:1370-1372; Hayetal. (1992) Hum. Antibod. Hybri response polypeptides. domas, 3:81-85; Huse et al. (1989) Science 246:1275-1281; 0297 To generate antibodies, a polypeptide or a fragment Griffith et al. (1993) EMBO J. 12:725-734. thereof is used as an epitope. In some embodiments, an 0303. The monoclonal antibodies are chimeric and epitope is at least 6 amino acids, at least 9 amino acids, at least humanized. Humanized monoclonal antibodies can be 20 amino acids, at least 40 amino acids, or at least 80 amino obtained using standard recombinant DNA techniques in acids in length. The epitope or polypeptide fragment can which the variable region genes (e.g., of a rodent antibody), comprise a domain, segment or motif that can be identified by are cloned into a mammalian expression vector containing the analysis using well-known methods, for example, signal appropriate human light change and heavy chain region polypeptides, extracellular domains, transmembrane seg genes. In this example, the resulting chimeric monoclonal ments or loops, ligand binding regions, Zinc finger domains, antibodies has the antigen-binding capacity from the variable DNA binding domains, acylation sites, glycosylation sites or region of the rodent but is significantly less immunogenic phosphorylation sites. because of the humanized light and heavy chain regions. See, 0298 Examples of antibodies contemplated by the present e.g., Surender K. Vaswani, Ann. (1998) Allergy Asthma. invention include polyclonal, monoclonal, humanized, chi Immunol. 81:105-119. meric, single chain antibodies, antibody fragments such as 0304 Any of the antibodies can further be coupled to a Fab fragments, F(ab')2 fragments, fragments produced by substance (label) for detection of a polypeptide-antibody FAb expression library, anti-idiotypic (anti-Id) antibodies and binding complex. Examples of labels include, enzymes, pros epitope-binding fragments of any of the above. thetic groups, fluorescent materials, luminescent materials, 0299 Polyclonal antibodies are prepared by immunizing a bioluminescent materials, or radioactive materials. Examples Suitable Subject (e.g., goats, rabbits, rats, mice or humans) of Suitable enzymes include, for example, horseradish per with a desired antigen. The antibody titer in the immunized oxidase, alkaline phosphatase, B-galactosidase, or acetylcho Subject can be monitored over time using methods known in linesterase. Examples of suitable prosthetic group complexes the art, such as by using an enzyme linked immunosorbent include, for example, streptavidin/biotin and avidin/biotin: assay (ELISA). The antibodies can then be isolated from the examples of suitable fluorescent materials include umbellif Subject (e.g., from blood) and further purified using tech erone, fluorescein, fluorescein isothiocyanate, rhodamine, niques, such as protein A chromatography, to obtain the IgG dichlorotriazinylamine fluorescein, dansyl chloride or phy fraction. coerythrin. An example of aluminescent material is luminol. 0300. At an appropriate time after immunization, such as Examples of bioluminescent materials include luciferase, when the antibody titers are highest, antibody-producing luciferin and aequorin. Examples of Suitable radioactive cells can be obtained from the subject and used for the prepa material include 125I, 131I, 35S or 3H. ration of monoclonal antibodies. Monoclonal antibodies are 0305. The antibodies can be used to isolate one or more populations of antibodies that contain only one species of an polypeptides of the invention, e.g., a drug response polypep antigen-binding site and are capable of immunoreacting with tide Such as an insulin sensitizer response polypeptides using only one particular epitope of insulin sensitizer response standard techniques such as affinity chromatography or polypeptides. A monoclonal antibody composition, there immunoprecipitation. The antibodies can also be used to fore, typically displays a single binding affinity for a particu detect the presence or absence of a particular polypeptide lar polypeptide with which it immunoreacts. (e.g., a polypeptide associated with a response to a drug Such 0301 There are numerous methods known in the art for as an insulin sensitizer) in a cell, cell lysate, cell Supernatant, producing monoclonal antibodies. In one example, mono tissue sample or elsewhere. In some embodiments, the anti clonal antibodies can be obtained by fusing individual lym bodies can further be used to inhibitor suppress the activity of phocytes (typically splenocytes) from an immunized animal Such polypeptides by specifically binding to the polypeptides. (typically a mouse or a rat) with cells derived from an immor tal B lymphocyte tumor (typically a myeloma) to produce a D. Screening Assays hybridoma. The culture supernatants of the resulting hybri 0306 The nucleic acids, polypeptides, antibodies and doma cells are screened to identify a hybridoma producing a other compositions herein may be utilized as reagents (e.g., in monoclonal antibody that specifically binds to a polypeptide pre-packaged kits) in the methods of the invention, e.g., for of interest. Other techniques for producing hybridoma screening prior to determining whether or not to administer a include the human B cell hybridoma technique described in drug, e.g., an insulin sensitizer to an individual. These may be Kozbor et al. (1983) Immunol. Today, 4:72; the EBV-hybri used alone or in combination, either with each other or with doma technique and the trioma techniques. phenotypic information related to the drug response. The 0302 Alternatively, monoclonal antibodies can be identi phenotypic information related to the drug response may be fied and isolated by Screening a combinatorial immunoglo determined in an association study as described above, or bulin library, such as an antibody phage display library. The may be phenotypic information previously known to be asso library can be screened with one or more of the polypeptides ciated with the drug response. Examples of Such phenotypic US 2008/0280955 A1 Nov. 13, 2008

information are detailed above and may include, e.g., medical target nucleic acid. Specific hybridization to a nucleic acid or history of an individual and/or relatives thereof (e.g., number variant associated with a response to an insulin sensitizer is an of years with type 2 diabetes, prior treatment regimens (e.g., indication that an individual will have the response if admin dosage of prior treatment with a glitaZone)), laboratory test istered an insulin sensitizer, which can be either the same results, and/or and simple measurements (e.g., weight, insulin sensitizer for which the individual is screened, or a height, girth, gender, etc.) Such screening can be used, for different insulin sensitizer. More than one probe can be used example, to identify individuals who may benefit (or not concurrently. benefit) from treatment with the drug, e.g., insulin sensitizer, 0313. In one embodiment, a nucleic acid probe is an allele individuals who may be enrolled (or excluded) from a clinical specific probe. See Saild, R. et al., (1986) Nature 324:163– trial, and/or individuals who may suffer (or not suffer) an 166. Allele-specific probes can used to identify the presence adverse reaction from the drug, e.g., insulin sensitizer. or absence of one or more variants in a test sample of DNA 0307. A variety of methods may be used to screen for obtained from an individual. A target nucleic acid is amplified response to a drug, e.g., an insulin sensitizer. The following using any method herein or known in the art. Flanking methods are provided as examples and not as limitations of sequences may also be amplified. In the case of Southern means to screen for response to a drug, e.g., an insulin sensi analysis, the amplified target nucleic acid is dot-blotted, using tizer. standard methods and the blot is then contacted with an allele specific nucleic acid probe. See Ausubel, F. et al., “Current E. Detection of Drug Response Nucleic Acids Protocols in Molecular Biology’ (eds. John Wiley & Sons). 0308 Screening steps of the methods of the invention can Detection of specific hybridization of an allele-specific probe include detection of presence, increased level or decreased to a target nucleic acid associated with a response to a drug, level of one or more nucleic acids, or fragments, derivatives, e.g., an insulin sensitizer is an indication that an individual variants or complements thereof, associated with a response will have the response if administered a drug, e.g. insulin to a drug, e.g., an insulin sensitizer. sensitizer. In some embodiments, the administered drug, e.g., 0309 Detection of nucleic acids and genetic variations in insulin sensitizer, is the same as the drug for which specific an individual may be made using any method known in the hybridization is detected. In other embodiments, the admin art. Examples of such methods include, for instance, Southern istered drug, e.g., insulin sensitizer, is a different drug but in or northern analyses, in situ hybridizations analyses, single the same drug class as the drug for which specific hybridiza Stranded conformational polymorphism analyses, poly tion is detected. Methods for preparing allele specific probes merase chain reaction analyses and nucleic acid microarray are known in the art. analyses. Such analyses may reveal both quantitative and 0314 Allele-specific probes are nucleic acids, mimetics, qualitative aspects of the expression pattern of drug response or a combination thereof, of approximately 10-50 base pairs polypeptides, e.g., insulin sensitizer response polypeptides. or approximately 15-30 base pairs that specifically hybridize In particular, Such analyses may reveal expression patterns or to one or more target nucleic acids. Target nucleic acids are polypeptides associated with a response to a drug, e.g., an any of the nucleic acids herein. insulin sensitizer. 0315. In one example, a target nucleic acid is a nucleic acid 0310. In one example, a diagnosis or prognosis is made associated with a drug response, e.g., a response to an insulin using a test sample containing genomic DNA or RNA sensitizer. Sets of nucleic acid probes that may be useful in obtained from the individual to be tested. The individual can identifying such target nucleic acids can be complementary to bean adult, child or fetus. The individual can be a human. The 1 or more, 2 or more, 3 or more, 4 or more, or 5 or more test sample can be from any source which contains genomic variants associated with a response to a drug, e.g., an insulin DNA or RNA including, e.g., blood, amniotic fluid, cere sensitizer. Such nucleic acid probes may be part of a set or in broSpinal fluid, skin, muscle, buccal or conjunctival mucosa, a kit (e.g., for use in Southern analysis or other techniques). placenta, gastrointestinal tract or other organs. A test sample Such nucleic acid probes can be allele-specific probes. of DNA from fetal cells or tissue can be obtained by appro 0316. Another method for detecting nucleic acids associ priate methods such as by amniocentesis or chorionic Villus ated with a response to a drug, e.g., a response to an insulin sampling, or from the mother's blood. The test sample is sensitizer, is northern analysis. Northern analysis can be used subjected to one or more tests to identify the presence or to identify gene expression patterns (e.g., mRNA) of drug absence of a nucleic acid of interest or a genetic variant of response polypeptides, e.g., insulin sensitizer response interest. polypeptides. See Ausubel, F. et al., “Current Protocols in 0311. In one embodiment, Southern blot, northern blot or Molecular Biology” (eds. John Wiley & Sons 1999). For similar analyses methods are used to identify the presence or northern analysis, a test sample of RNA is obtained from an absence of a nucleic acid of interest or a genetic variant of individual by appropriate means. Specific hybridization of a interest using complementary nucleic acid probes associated nucleic acid probe that is complementary to the RNA with a response to a drug, e.g., an insulin sensitizer. The sequence encoding a polypeptide associated with a response nucleic acid probes can be labeled before being contacted to a drug, e.g., an insulin sensitizer is an indication that an with the sample. individual will have the response if administered the drug, 0312. In hybridization analysis, the sample is maintained e.g., insulin sensitizer, or another drug in the same class of under conditions sufficient to allow for specific hybridization drugs. A nucleic acid probe can be labeled. A nucleic acid of the nucleic acid probe to the target nucleic acid. In one probe can be an allele-specific probe, or may include kits or embodiment, the labeled nucleic acid probe and target nucleic collections of probes with more than one of such probes. acid specifically hybridize with no mismatches. Specific 0317. Alternative diagnostic and prognostic methods hybridization can be performed under stringent conditions employ amplification of target nucleic acids associated with a disclosed herein and can be detected using standard methods. response to a drug, e.g., an insulin sensitizer, e.g., by PCR. Hybridization is indicative of the presence or absence of a This is especially useful for the target nucleic acids present in US 2008/0280955 A1 Nov. 13, 2008 44 very low quantities. In one embodiment, amplification of be grouped within a single microarray or in multiple separate target nucleic acid probes associated with a response to a microarrays so that varying optimal conditions may be used drug, e.g., an insulin sensitizer indicates their presence and is during the hybridization of the target to the microarray. For an indication that an individual will have the response if example, it may be desirable to provide for the detection of administered the drug, e.g., insulin sensitizer, or if adminis polymorphisms that fall within G-C rich stretches of a tered another drug in the same class of drugs. In another genomic sequence separately from those that fall in A-Trich embodiment, allele specific primers are use to amplify segments for optimization of hybridization conditions. Addi genomic DNA associated with a response to a drug, e.g., an tional description of use of nucleic acid microarrays for insulin sensitizer as an indication that an individual will have detection of polymorphisms can be found, for example, in the response if administered the drug, e.g., insulin sensitizer, U.S. Pat. Nos. 5,858,659 and 5,837,832, the entire teachings or another drug in the same class. of which are incorporated by reference herein. 0318. In another embodiment, cDNA is obtained from 0322. Other methods to detect variant nucleic acids target RNA nucleic acids by reverse transcription. Nucleic include, for example, direct manual sequencing (Church and acid sequences within the cDNA are then used as templates Gilbert, (1988) Proc. Natl. Acad. Sci. USA 81: 1991-1995; for amplification reactions. Nucleic acids used as primers in Sanger, F. et al. (1977) Proc. Natl. Acad. Sci. USA 74:5463 the reverse transcription and amplification reaction steps can 5467; and U.S. Pat. No. 5.288,644); automated fluorescent be chosen from any of the nucleic acids herein. For detection sequencing; single-stranded conformation polymorphism of amplified products, the nucleic acid amplification may be assays: clamped denaturing gel electrophoresis; denaturing performed using labeled nucleic acids. Alternatively, enough gradient gel electrophoresis (Sheffield, V. C. et al. (1981) amplified product may be made such that the product may be Proc. Natl. Acad. Sci. USA86:232-236), mobility shift analy visualized by standard ethidium bromide staining or by uti sis (Orita, M. et al. (1989) Proc. Natl. Acad. Sci. USA lizing other Suitable nucleic acid staining method. 86:2766-2770), restriction enzyme analysis (Flavell et al. 0319 Microarrays can also be utilized for screening for (1978) Cell 15:25; Geever, et al. (1981) Proc. Natl. Acad. Sci. responsiveness to a drug, e.g., an insulin sensitizer. Microar USA 78:5081); heteroduplex analysis; chemical mismatch rays comprise probes that are complementary to target cleavage (Cotton et al. (1985) Proc. Natl. Acad. Sci. USA nucleic acid sequences from an individual. A microarray 85:4397–4401); RNase protection assays (Myers, R. M. et al. probe can be allele specific. In one embodiment, the microar (1985) Science 230:1242); and use of polypeptides which ray comprises a plurality of different probes, each coupled to recognize nucleotide mismatches, such as E. coli mutS pro a surface of a substrate in different known locations and each, tein. capable of binding complementary Strands. See, e.g., U.S. Pat. No. 5,143,854 and PCT Publication Nos. WO 90/15070 F. Detection of Drug Response Polypeptides and WO92/10092. These microarrays can generally be pro 0323 Detecting the presence, level of expression, activity duced using mechanical synthesis methods or light directed and location of a drug response polypeptide, e.g., insulin synthesis methods that incorporate a combination of photo sensitizer response polypeptides, may also be used as a lithographic methods and Solid phase oligonucleotide synthe screening tool to determine whether or not an individual will sis methods. See Fodor et al., (1991) Science 251:767-777: respond to a drug, e.g., an insulin sensitizer. Briefly, detection and U.S. Pat. No. 5,424,186. Techniques for the mechanical of the presence, level of expression or enhanced activity of synthesis of microarrays are described in, for example, U.S. polypeptides associated with a response to a drug, e.g., an Pat. No. 5,384,261. insulin sensitizer is an indication that an individual will have 0320 Once a microarray is prepared, a target or sample the response if administered the drug, e.g., insulin sensitizer, nucleic acid (e.g., DNA or RNA) is hybridized to the microar or another drug in the same class. Proteins may be analyzed ray before the microarray is scanned. Typical hybridization from any tissue or cell type. Analyses can be made in vivo or and scanning procedures are described in PCT Publication in vitro. Nos. WO 92/10092 and WO95/11995, and U.S. Pat. No. 0324 Methods to detect and isolate polypeptides are 5,424,186. Briefly, target nucleic acid sequences that include known to those of skill in the art and include, for example, one or more previously identified variants or polymorphisms enzymes linked immunosorbent assays (ELISAS), immuno are amplified (optional) and labeled by well-known amplifi precipitations, immunofluorescence, immunoblotting, west cation techniques, such as PCR. Primers that are complemen ern blotting, spectroscopy, colorimetry, electrophoresis and tary to both Strands of the target sequence (upstream and isoelectric focusing. See U.S. Pat. No. 4,376,110; see also downstream from a variant or polymorphism) may be used to Ausubel, F. et al., “Current Protocols in Molecular Biology’ amplify the target region. Asymmetric PCR techniques may (Eds. John Wiley & Sons, chapter 10). Protein detection and be used. After labeling with a detectable tag, the target nucleic isolation methods employed may also be those described in acid is hybridized with the microarray under appropriate con Harlow and Lane (Harlow, E. and Lane, D., “Antibodies: A ditions. Upon completion of hybridization and washing and/ Laboratory Manual. Cold Spring Harbor Laboratory Press, or staining of the microarray, the microarray is scanned to Cold Spring Harbor, N.Y., 1998). determine the position on the microarray to which the target 0325 In one embodiment, the presence, amount and loca sequence hybridizes. The hybridization data obtained from tion of polypeptides associated with a response to an insulin the scan is typically in the form of fluorescence intensities as sensitizer can be determined using a probe oran antibody that a function of location on the microarray. specifically binds one or more polypeptides associated with 0321 Although primarily described in terms of a single the response to the insulin sensitizer. detection block, such as for the detection of a single polymor 0326 In one embodiment, a probe or antibody is labeled phism, microarrays can include multiple detection blocks, directly or indirectly. Direct labeling involves coupling and thus be capable of analyzing multiple specific polymor (physically linking) a detectable Substance to an antibody or phisms. In an alternative arrangement, detection blocks may a probe. Indirect labeling involves the reactivity of the probe US 2008/0280955 A1 Nov. 13, 2008 with another reagent that is directly labeled. An example of may be accomplished by removing a histological specimen indirect labeling includes, for example, detection of a primary from a patient, such as by biopsy. The specimen is then antibody using a fluorescently labeled secondary antibody applied with a labeled antibody described herein. The anti and end labeling of a DNA probe with biotin such that it can body or fragment can be applied by overlaying the labeled be detected with fluorescently labeled streptavidin. antibody or fragment onto the sample. This procedure allows 0327. A solid support may be utilized to immobilize either for the determination of the presence, absence, amount and the antibody or probe or the sample. In one example, a sample location of a polypeptide of interest. may be immobilized onto a solid Support such as a flat Sur 0331. The antibody can also be detectably labeled using face, columns, beads, optical fibers etc., which is capable of fluorescence emitting metals such as 152Eu, or others of the immobilizing cells, cell particles, or soluble proteins. The lanthanide series. These metals can be attached to the anti support may then be washed with suitable buffers followed by body using Such metal chelating groups as diethylenetri treatment with a detectably labeled antibody. The amount of aminepentacetic acid (DTPA) or ethylenediaminetetraacetic bound labeled antibody on the solid support may then be detected by conventional means. Well known supports acid (EDTA). include glass, polystyrene, polypropylene, polyethylene, 0332 The antibody also can be delectably labeled by cou dextran, nylon, amylases, natural and modified celluloses, pling it to a chemiluminescent compound. The presence of polyacrylamides, gabbros, nitrocellulose and magnetite. the chemiluminescent-tagged antibody is then determined by 0328. The antibodies herein can be linked to an enzyme detecting the presence of luminescence that arises during the and used in enzyme immunoassay. See Voller, “The Enzyme course of a chemical reaction. Examples of particularly useful Linked Immunosorbent Assay (ELISA), Diagnostic Hori chemiluminescent labeling compounds are luminol, isolumi Zons 2:1-7 (Microbiological Associates Quarterly Publica nol, theromatic acridinium ester, imidazole, acridinium salt tion, Walkersville, Md. 1978); Maggio, “Enzyme Immunoas and oxalate ester. say' (CRC Press, Boca Raton, Fla. 1980); Ishikawa, et al., 0333. Likewise, a bioluminescent compound may be used “Enzyme Immunoassay” (Kgaku Shoin, Tokyo, 1981). The to label the antibodies herein. Bioluminescence is a type of enzyme which is bound to the antibody will react with an chemiluminescence found in biological systems in which a appropriate Substrate, e.g., a chromogenic Substrate, in Such a catalytic protein increases the efficiency of the chemilumi manner as to produce a chemical moiety which can be nescent reaction. The presence of a bioluminescent protein is detected, for example, by spectrophotometric, fluorimetric or determined by detecting the presence of luminescence. In by visual means. Enzymes that can be used to label the anti Some embodiments, the bioluminescent compounds for pur body include, but are not limited to, malate dehydrogenase, poses of labeling antibodies are luciferin, luciferase and staphylococcal nuclease, delta-5-steroid isomerase, yeast aequorin. alcoholdehydrogenase, alpha-glycerophosphate, dehydroge 0334. In one embodiment, the presence (or absence) of a nase, triose phosphate isomerase, horseradish peroxidase, polypeptide associated with a response to a drug, e.g., an alkaline phosphatase, asparaginase, glucose oxidase, beta insulin sensitizer in a sample (e.g., a cell, cell lysate, tissue, galactosidase, ribonuclease, urease, catalase, glucose-6- whether in vivo or in vitro) can be established by contacting phosphate dehydrogenase, glucoamylase and acetylcho the sample with an antibody and then detecting a binding linesterase. Detection can be accomplished by calorimetric complex. The presence of a polypeptide associated with a methods which employ a chromogenic Substrate for the response to a drug, e.g., an insulin sensitizer in a sample is an enzyme. Detection can also be accomplished by visual com indication that an individual will have the response if admin parison of the extent of enzymatic reaction of a Substrate in istered the drug, or another drug in the same class, e.g., comparison with similarly prepared standards. another insulin sensitizer. 0329 Detection may also be accomplished using any of a 0335. In another embodiment, the level of expression or variety of other immunoassays. For example, by radioac composition of a polypeptide associated with a response to a tively labeling the antibodies or antibody fragments, it is drug, e.g., an insulin sensitizer in a test sample is compared possible to detect fingerprint gene wild type or mutant pep with the level of expression of the same polypeptide in a tides through the use of a radioimmunoassay. See Weintraub, control sample. A control sample can be a known level of B., “Principles of Radioimmunoassays, Seventh Training expression of the polypeptide, or a level of expression in a Course on Radioligand Assay Techniques” (The Endocrine sample from an individual with a known response to the drug, Society, March, 1986). The radioactive isotope can be e.g., insulin sensitizer. detected by Such means as the use of a gamma counter or a 0336 Alterations in the level of expression or composition Scintillation counter or by autoradiography. of a drug response polypeptide, e.g., an insulin sensitizer 0330. It is also possible to label the antibody with a fluo polypeptide may be indicative that an individual will have the rescent compound. When the fluorescently labeled antibody response if administered the drug, e.g., insulin sensitizer, or is exposed to light of the proper wave length, its presence can another drug in the same class. In one example, a test sample be detected due to fluorescence. Among the most commonly from an individual is assessed for a change in expression (e.g., used fluorescent labeling compounds are fluorescein isothio level of transcription) and/or composition (e.g., splicing vari cyanate, rhodamine, phycoerythrin, phycocyanin, allophyco ants) of a polypeptide associated with a response to a drug, cyanin, o-phthaldehyde and fluorescamine. The fluorescently e.g., an insulin sensitizer. Detection of an increased level of labeled antibody can be coupled with light microscopic, flow expression of a polypeptide associated with a response to a cytometric or fluorimetric detection. In one example, anti drug, e.g., an insulin sensitizer may be an indication of an bodies, or fragments thereof, may be employed histologi increased probability that the individual will respond to the cally, as in immunofluorescence or immunoelectron micros drug, e.g., insulin sensitizer, or to another drug in the same copy, for in situ detection of a polypeptide associated with a class. On the contrary, detection of a reduced level of a response to drug, e.g., an insulin sensitizer. In situ detection polypeptide associated with a response to a drug, e.g., an US 2008/0280955 A1 Nov. 13, 2008 46 insulin sensitizer may be indicative of, for example, a reduced ents, binders, lubricants, coloring matters, disintegrators and probability that the individual will respond to the drug, e.g., the like can be used upon preparing Solid preparations for oral insulin sensitizer. administration. 0341 Excipients include, for example, lactose, starch, talc, magnesium Stearate, microcrystalline cellulose, methyl VI. Detection of Drug Response Phenotypes cellulose, carboxymethylcellulose, glycerol, Sodium alginate and arabic gum. Binders used include polyvinyl alcohol, 0337 Association studies using genetic variations as well polyvinylether, ethyl cellulose, arabic gum, shellac and as phenotypic variations are described in U.S. patent appli Sucrose, and lubricants used include magnesium Stearate, and cation Ser. No. 11/043,689, filed Jan. 24, 2005, entitled talc. Further, coloring materials and disintegrators known in “Associations. Using Genotypes and Phenotypes” which is the art can be used. Tablets may be coated by well known incorporated herein by reference. methods. 0338. Data on a one or more phenotypes can be measured 0342. Liquid preparations may be acqueous or oily Suspen or received (e.g., from a database or medical records). Data on Sion, Solution, syrup, elixir and the like, and they can be the group of phenotypes can be measured or received prior to, prepared by conventional methods. When injectable prepara after, and/or concurrent with the generation of the genetic tions are formulated, to the compounds of the present inven association data. In some embodiments, data on the pheno tion may be added pH regulating agent, buffering agent, sta types is generated by a practitioner of the present invention bilizing agent, isotonicity, local anesthetic and the like and by, for example, observation (e.g., gross phenotypic trait Such then preparations for Subcutaneous, intramuscular or intrave as height, weight, BMI, gender, malformation or other physi nous injections can be made by conventional methods. When cal abnormality, etc.), biochemical testing (e.g., blood or a Suppository is made, oily bases such as cacao butter, poly urine analysis), or other diagnostic test (e.g., X-ray, MRI, ethylene glycols. Witepsol. RTM. (Dynamite Nobel Com CAT scan, CT scan, Doppler shift, etc.) Additional examples pany) and the like may be used as base. of phenotype data that may be received/collected about indi 0343 Preparations for other types of administration, such viduals can include phenotype data about previous medical as by inhalation, transdermally, intranasally, intrabuccally, conditions or medical history (e.g., whetheran individual has and the like, are known in the art and may also be used with a had surgery, experienced a particular illness, given vaginal or drug, Such as an insulin sensitizer, that is administered nonvaginal childbirth, been diagnosed with mental illness, according to the methods of the invention. See, e.g., Reming has allergies, etc.). In some embodiments, phenotype data tons Pharmaceutical Sciences, 20th Ed., Lippincott Williams may also be received/collected on the individuals family & Wilkins., 2000. history. For example, data can be collected on relatives exhib 0344. The dosage of such preparations is varied depending iting a given phenotype (e.g., a particular drug response or upon the condition, body weight, age, etc. of the patient and is disease, etc.) not the same for all the patients. In some embodiments, it is set such that the dosage of the compounds of the present VII. Treatments invention is in the range of about 0.01 to 2000 mg/day per adult patient, or about 0.1 to 1000 mg/day per adult patient, or 0339 Methods of the invention can include treating, or not about 0.1 to 500 mg/day per adult patient, or about 0.5 to 300 treating, an individual based on the results of a screening step mg/day per adult patient, or about 1 to 250 mg/day per adult to determine if the individual is responsive to a drug, e.g., an patient, or about 1 to 150 mg/day per adult patient, or about 5 insulin sensitizer. Treatment includes administering or not to 150 mg/day per adult patient, or about 10 to 120 mg/day per administering a drug, e.g., an insulin sensitizer. In some adult patient, or about 5 to about 250 mg/day per adult patient, embodiments, the drug, e.g., insulin sensitizer, for which the or about 20 to about 240 mg/day per adult patient, or about 40 individual is screened, is the same as the drug that is admin to about 220 mg/day per adult patient, or about 60 to about istered or not administered. In some embodiments, the drug, 180 mg/day per adult patient, or about 80 to about 160 mg/day e.g., insulin sensitizer, for which the individual is screened, is per adult patient. The preparation can be divided and admin a different drug (e.g., in the same class as the drug that is istered from one to four times per day. In some embodiments, administered or not administered). Thus, in some embodi the preparation is administered about once per week, or about ments a drug, e.g., an insulin sensitizer is administered to the twice per week, or about three times per week, or about four individual based on the results of the screening step. In other times per week, or about five times per week, or about six embodiments, a drug, e.g., an insulin sensitizer is not admin times per week. In some embodiments, the preparation is istered to the individual based on the results of the screening administered about once per day. In some embodiments, the step. The administration or lack of administration may be in preparation is administered about twice per day. conjunction with other treatments, such as the use of another 0345. In some embodiments, the preparation contains an drug, e.g., another insulin sensitizer, or other drugs. The insulin sensitizer. In some embodiments, the insulin sensi administration or lack of administration may be in a clinical tizer is a TZD PPAR modulator. In some embodiment, the setting as part of the course of treatment of the condition (e.g., insulin sensitizer is netoglitaZone. In some embodiments, the insulin resistance disorder) and/or as part of a study, e.g., a insulin sensitizer is given in a dose of 1 to 200 mg/day per clinical trial. adult patient. In some embodiments, the TZD-PPAR modu 0340 Drugs, such as insulin sensitizers and other thera lator is given in a dose of about 1 to 200 mg/day per adult peutic agents used for treatment can be formulated to various patient. In some embodiments, the netoglitaZone is given in a preparations Suitable for various administration routes, using dose of about 5 to about 250 mg/day per adult patient, or about conventional carriers. For example, for oral administration, 20 to about 240 mg/day per adult patient, or about 40 to about they are formulated in the form of tablet, capsule, granule, 220 mg/day per adult patient, or about 60 to about 180 mg/day powder, liquid preparation and the like. Conventional excipi per adult patient, or about 80 to about 160 mg/day per adult US 2008/0280955 A1 Nov. 13, 2008 47 patient. In Such embodiments, the insulin sensitizer, e.g., a primer, a probe, an immunoassay, a chip based DNA assay, a TZD-PPAR modulator such as netoglitazone, can be given in PCR assay, a Taqman Massay, a sequencing based assay, and a formulation that includes mannitol, a fluidizing agent, e.g., the like. In some embodiments, such tools can provide means talc, a disintegrant, e.g., crosprovidone, a lubricant, e.g., mag for detecting 1 or more genetic variations, or 3 or more nesium Stearate, and additional ingredients such as hydrox genetic variations, or 30 or more genetic variations, or 300 or ypropylcellulose, propylene glycol, and titanium dioxide. more genetic variations, or 3,000 or more genetic variations, 0346. In one embodiment, the drug administered is or 30,000 or more genetic variations, or 300,000 or more netoglitazone, given in a once-daily oral dose of 80-160 genetic variations, or 3,000,000 or more genetic variations. In mg/day, and prepared in a formulation that is about 68%- Some embodiments, such genetic variations are SNPs. 78%, d-mannitol, about 0.1 to about 2% talc, about 3-7% 0351. In some embodiments, a diagnostic tool that identi crosprovidone, about 2-4% hydroxypropylcellulose, about fies genetic variations scans at least about 10,000 bases, at 1-3% magnesium Stearate, coated with a film that is about least about t20,000 bases, at least about 50,000 bases, at least 1-3% (oftotal weight) hydroxypropylcellulose, about 0.1-1% about 100,000 bases, at least about 200,000 bases, at least propylene glycol, about 0.2-2% titanium dioxide, and about about 500,000 bases, at least about 1,000,000 bases, or at least 0.1-0.5% talc, with the remainder active ingredient, i.e., about 2,000,000 bases, at least about 5,000,000 bases, at least netoglitaZone (all percentages are w/w; percentages are given about 10,000,000 bases, at least about 20,000,000 bases, at for tablet containing 20 mg netoglitaZone and would be least about 50,000,000 bases, at least about 100,000,000 adjusted as appropriate for other sizes, e.g., 5 mg or 10 mg). bases, at least about 200,000,000 bases, at least about 500, In one embodiment the drug administered in netoglitaZone, 000,000 bases, at least about 1,000,000,000 bases, at least given in a once-daily oral dose of 80-160 mg/day, and pre about 2,000,000,000 bases, or at least about 3,000,000,000 pared in a 20 mg formulation that is about 73%, d-mannitol, bases of genetic material from an individual. In some embodi about 1% talc, about 5.2% crosprovidone, about 3.2% ments, all, or Substantially all, of an individual's genome is hydroxypropylcellulose, about 2.1% magnesium Stearate, scanned, e.g., sequenced. In certain embodiments, not all coated with a film that is about 2.4% (oftotal weight) hydrox associated SNPs need to be scanned to determine if an indi ypropylcellulose, about 0.5% propylene glycol, about 0.7% vidual is or is not responsive to a drug, e.g., an insulin sensi titanium dioxide, and about 0.3% talc, with the remainder tizer. active ingredient, i.e., netoglitaZone (percentages for 20 mg 0352. In some embodiments a diagnostic tool that identi tablet). fies genetic variations scans less than about 100,000,000 0347 In some embodiments, the administration of the bases, less than 50,000,000 bases, less than 10,000,000 bases, drug, e.g., insulin sensitizer is modulated based on the results less than 5,000,000 bases, less than 2,000,000 bases, less than of the screening step. Such modulations are as described 1,000,000 bases, less than 500,000 bases, less than 200,000 herein. bases, less than 100,000 bases, less than 50,000 bases, less than 20,000 bases, less than 10,000 bases, less than 5,000 VIII. Kits bases, less than 2,000 bases, less than 1,000 bases, less than 0348. The present invention also contemplates kits for 500 bases, less than 200 bases, less than 100 bases, less than predicting if an individual responds or does not respond to a 50 bases, less than 20 bases or less than 10 bases. drug, e.g., an insulin sensitizer. Such kits can be used, for 0353. In some embodiments, SNPs scanned and geno example, to identify individuals who may benefit (or not typed from part or all of the genome using a kit of the inven benefit) from treatment with a drug, e.g., insulin sensitizer, tion are used in an association study. In other embodiments, individuals who may be enrolled (or excluded) from a clinical only a subset of those SNPs scanned are used in an association trial, and/or individuals who may suffer (or not suffer) an study. adverse reaction from a drug, e.g. insulin sensitizer. In some 0354. In some embodiments, a diagnostic tool includes in embodiments the drug, e.g., insulin sensitizer, for which the a kit of the invention provides means for detecting and/or kit is used is the same as the drug for which a prediction is quantifying one or more phenotypes (e.g., protein expression, made as to the individual's response. In some embodiments clinical test results, medical history, simple measurements, the drug, e.g., insulin sensitizer, for which the kit is used is a etc.) in an individual. Examples of Such diagnostic tools different drug in the same class as the drug for which a include, but are not limited to blood tests (e.g., PSA, blood prediction is made as to the individual's response. glucose levels, etc.); other biochemical tests (e.g., pregnancy 0349 The kits herein can include at least one diagnostic tests, allergy tests, etc.), self-diagnosis tests (e.g., breast tool in Suitable packaging. In some embodiments the kit exam, skin exam, IQ exam, etc.); review of medical history further contains a set of written instructions. Kits useful in (e.g., number of years with type 2 diabetes, prior treatment screening, diagnosis and prognosis include reagents compris regimens, etc.) and simple measurements (e.g., weight, ing, for example, nucleic acid probes or primers (for ampli height, girth, gender, etc.) fication, reverse transcriptase and detection), restriction 0355. In some embodiments, a kit comprises at least two enzymes (e.g., for RFLP analysis), allele-specific probes, and diagnostic tools: one to detect and/or quantify genetic varia antisense nucleic acids, antibodies and other protein binding tion(s) in an individual and one to detect and/or quantify probes, any of which may be labeled. Kits may also comprise phenotypic trait(s) of the individual. In some embodiments, instructions and apparati for performing phenotypic analyses, the written instructions provide guidelines for using the the results of which may be used in combination with nucleic results from the diagnostic tools to predict whether an indi acid or protein analyses. vidual has or does not have a phenotype-of-interest. 0350. In some embodiments, the diagnostic tool provides 0356. The results of the association studies and/or kits means for identifying one or more genetic variations in an herein can be used, directly or indirectly, in drug discovery, individual. Examples of diagnostic tools that can be used to clinical trials and other discovery efforts with partners. In identify genetic variations include, but are not limited to, a Some embodiments, the present invention contemplates com US 2008/0280955 A1 Nov. 13, 2008 48 puter readable databases comprising data on genetic varia serotonin reuptake inhibitors), TCAS (tricyclic antidepres tions and, in Some embodiments, a group of phenotypes of sants), MAOIs (monoamine oxidase inhibitors), and triazol individuals. The databases can be accessible on-line or by opyridines. Association studies may be performed to identify other medium. The databases can be used to perform virtual polymorphic loci associated with the efficacy of each of these association studies to correlate phenotypes and/or genotypes types of drugs, and those loci could then be used to Screen with a phenotype-of-interest. For example, in Some embodi patient populations to determine which class of drugs would ments, databases herein can be used to perform virtual asso be most efficacious for a given individual. For each drug, a ciation studies by using one of the phenotypes as a phenotype case group comprises individuals with depression that had an efficacious response to the drug, and a control group com of-interest in a new study. prises individuals that did not have an efficacious response to 0357 For example, the association studies and/or kits the drug. Associated SNPs are identified as those that have a herein can be used to predict if an individual will or will not significantly differentallele frequency in the cases than in the have a response to a drug, e.g., an insulin sensitizer based on controls. For each class of drug, thresholds are determined their genotypes at a set of SNPs or subset thereof and/or a set that will identify individuals with a high (e.g. >80%, or >90% or Subset of phenotypes. or >95%, or >98%) chance of having an efficacious response. 0358. In some embodiments, such a response to a drug, An individual in need of antidepressant therapy is screened e.g., an insulin sensitizer may be to a drug or product that has for the SNPs that are associated with each of the drug types, been pulled off the market due to unpredictable adverse and a clinician determines an appropriate therapy choice for effects in a small group of individuals or to one that did not the individual based on the individual's genotype information obtain regulatory approval due to a large number of individu and the thresholds determined for each class of drug. As will als experiencing unanticipated effects in clinical trials. In be apparent, the same sort of studies and screening may be Some embodiments, such a response to a drug, e.g., an insulin done for insulin sensitizer drugs. sensitizer may be to a drug or product that is different from, but in the same class as, a drug that has been pulled off the IX. Business Methods market due to unpredictable adverse effects in a small group 0363 The invention also provides business methods. of individuals or to one that did not obtain regulatory approval 0364 Information concerning the characteristics (effec due to a large number of individuals experiencing unantici tiveness, safety, and efficiency) of a given drug, e.g., insulin pated effects in clinical trials. sensitizer is extremely valuable to the pharmaceutical indus 0359. In some embodiments, the response may be an try and can save a company Substantial money in lost revenue adverse response, and the studies and/or kits may be used to due to failures in clinical trials. The information may be used exclude individuals predicted to have an adverse response in decisions regarding the drug itself, or in decisions regard from treatment or from a research study, e.g., a clinical trial, ing another drug in the same class of drugs, or both. Such as a clinical trial to study a new drug or a clinical trial to 0365 Thus, in some embodiments, a collaborator or part study a drug that has been pulled of the market or that did not ner (e.g., a drug company) can use the association studies or obtain regulatory approval. Alternatively. Such individuals kits herein to correlate between genomic and/or phenotype may be treated or included in the study, but appropriate differences, and insulin sensitizer response (or lack thereof) adjustments may be made in their treatment based on the or insulin sensitizer tolerance. Furthermore, the ability to predicted adverse effect. In some embodiments, the response predict an insulin sensitizer response, can Subsequently be is an adverse response and a decision to treat or not treat the used to stratify patients into various groups. The groups may be, for example, those that respond to an insulin sensitizer individual with the drug is based on a combination of factors Versus those that do not respond, or those that respond to an that may include the likelihood of the adverse response, the insulin sensitizer without toxic effects versus those that are type of adverse response, the severity of the disease or con observed to have toxic effects. This may be useful for such dition for which the individual is being treated, and other company to overcome negative clinical trial results, obtain clinical criteria. regulatory approval faster, and recoup losses. This can also 0360. In some embodiments, the response may be a thera save millions of dollars in unsuccessful clinical trials and peutic response, and the individual is selected for treatment or fruitless research and development efforts. for inclusion in a research study based on the predicted thera 0366 Thus, in one embodiment, a therapeutic may be peutic effect. A prognosis based on the predicted response marketed with a kit as disclosed herein that is capable of may also be made. In some embodiments, other treatments segregating individuals that will respond in an acceptable may be used or not used in conjunction with the drug, based manner to a drug from those that will not (e.g., individuals on the predicted therapeutic response. who will experience adverse side effects, minimal beneficial 0361. In some embodiments, the association studies and/ effects or no beneficial effects). Additional methods of using or kits herein can be used to assist in determining a course of an association study for pharmacogenomics are disclosed in treatment for an individual, based on their genotypes at a set e.g., U.S. Provisional No. 60/566,302, filed Apr. 28, 2004, of SNPs or subset thereofand/or a set or subset of phenotypes. and entitled “Methods of Genetic Analysis”; U.S. Provisional In some embodiments, the association studies and/or kits No. 60/590,534, filed Jul. 22, 2004, and entitled “Methods of herein can be used to assess whether a brand name drug Genetic Analysis”; and U.S. Provisional No. 10/956.224, should be used, or if a cheaper generic may be substituted filed Sep. 30, 2004, and entitled “Methods of Genetic Analy instead, based on their genotypes at a set of SNPs or subset sis', which are incorporated herein in their entirety by refer thereof and/or a set or Subset of phenotypes. For example, an ence for all purposes. association study can be performed to identify genetic loci associated with a positive clinical response to the generic X. Example alternative. 0367 Reference now will be made in detail to various 0362 For example, there are a multitude of drugs on the embodiments and particular applications of the invention. market for treating depression including SSRIs (selective While the invention will be described in conjunction with the US 2008/0280955 A1 Nov. 13, 2008 49 various embodiments and applications, it will be understood isolated target sequences, which can be used as needed for the that Such embodiments and applications are not intended to application at hand. Samples Subjected to selection probe limit the invention. On the contrary, the invention is intended amplification were fragmented prior to labeling using DNaseI to cover alternatives, modifications and equivalents that may in 1x One-Phor-All Buffer Plus (GE Healthcare). The reac be included within the spirit and scope of the invention. tion was incubated at 37°C. for 6 minutes, followed by a 95° 0368. An association study was performed to identify C. incubation for 5 minutes. Following fragmentation, the SNPs associated with edema in response to treatment with samples were labeled. To each fragmented DNA sample, 4 ul glitaZones, in particular pioglitaZone (Actos) and rosiglita of 0.5 mMbiotin mix (ddUTP/dUTP:Roche) and 2 ulofrTdT Zone (Avandia). Findings from this study provide an oppor (400 U/ml; terminal deoxynucleotidyl transferase: Roche) tunity for increased understanding of human biology, disease were added. The plate was sealed with a clear, plastic Seal, and drug effects. Of particular interest is the use of the genetic vortexed briefly, and spun down in a SORVALL centrifuge for loci identified for the development of pharmacogenomic 15 seconds at 1000 rp.m. The plate was placed into a ther based tests to guide drug selection and to target therapy for mocycler and incubated at 37°C. for 90 minutes, followed by selected patient Subsets. a 95°C. incubation for 5 minutes. After the 95°C. incubation, 0369 Saliva samples were collected from 823 subjects the plate was held at 4°C. who experienced edema while on thiazolidinedione therapy 0372. The remaining ~/3 of the samples were amplified and 2177 subjects who did not (for use as controls). The DNA using multiplex (-232-plex) short-range PCR (SR-PCR). from these subjects was used in a whole genome association Multi-well (384-well) primer plates, each containing ~464 study for discovery of SNPs associated with edema secondary primers per well, were allowed to thaw at room temperature to thiazolidinedione therapy. for 15 minutes and were spun down for one minute at 1000 0370. Two board-certified physicians adjudicated the r.p.m. in the SORVALL centrifuge. Tubes containing target edema cases used in the while genome analysis. The follow DNA were spun down for 20 seconds at 14,000 rp.m. in the ing criteria were used for selecting the edema cases: severity EPPENDORF centrifuge. The short-range PCR (SR-PCR) ofedema (trace or mild cases were excluded), clinical assess reactions contained 0.061 M Trizma, 0.017 M (NH)SO, ment VS Subject complaint (physician assessment required), 3.7 mM MgCl, 0.03 M Tricine, 0.56x Enhancer (Epicenter and medical intervention was involved to address the edema Technologies), 4% DMSO, 0.05 M KC1, 0.542 mM each (specifically, the glitaZone dose was decreased, the glitaZone dNTP 2.08x TITANIUMTM Taq DNA polymerase (Clon dose was discontinued, or a diuretic was initiated). Of the tech), 3.3 LM of each PCR primer (a total of ~464 primers, or edema cases collected, 666 were chosen for genotyping based ~232 primer pairs), 15 ng target DNA, and enough MILLI on these adjudication criteria. Of the controls collected, 1726 PORE water to make the final volume 6 ul. SR-PCR was were matched (on a population basis) to the edema cases by performed in the 384-well primer plates (now referred to as sex, drug and dose, ethnicity, and insulin useand were geno “PCR plates”), which were sealed (using the PlateLoc at 173° typed. Approximately 1000 randomly selected SNPs were C. for 2.5 seconds (Velocity 11, Menlo Park, Calif.)), placed used to evaluate population structure in the samples, and to on ice, centrifuged at 1000 rp.m. for 15 seconds in a table-top adjust for ancestry in association analyses (Price, A. L., SORVALL centrifuge, Vortexed for six seconds, and spun Patterson, N.J., Plenge, R. M., et al (2006) Principal compo down again at 1000 rp.m. for 15 seconds. The sealed PCR nents analysis corrects for stratification in genome-wide asso plates were stored on ice prior to amplification. Thermocy ciation studies. Nature Genetics 38,904-909). Each subject's clers were preheated to 90° C. prior to placing the PCR plates DNA sample was individually genotyped to interrogate 287, into the machines. The short-range PCR program is provided 161 SNPs across the entire genome. These SNPs were in Table 12. selected to tag bins of common SNPs in linkage disequilib 0373) Once the PCR was complete, the PCR plates were rium for both Caucasian and Asian populations; it has been removed from the machines and were either subjected to shown that such SNP subsets capture much of the common pooling immediately or were stored at 4° C. (if the PCR variation across the genome (Hinds, D. A. Stuve, L. L., products were to be stored for longer than one week, they Nilsen, G. B., et al (2005). Whole-genome patterns of com were stored at -20°C. mon DNA variation in three human populations. Science 307, 1072-1079). TABLE 13 0371. A total of 666 cases and 1726 controls were geno typed, and the resulting genotypes were analyzed to identify Short-range PCR program SNP alleles and/or haplotypes associated with incidence of edema. All of the samples were amplified. Approximately 2/3 Temperature Time # cycles of the samples were amplified using 'selection probe ampli 96° C. 5 min. 1 fication' (see U.S. patent application Ser. No. 11/058,432, 96° C. 2 Sec. 55 filed Feb. 14, 2005, entitled “Selection Probe Amplifica 53o C. 2 min. tion'). In brief, selection probe amplification is a technique 50° C. 15 min. 1 for isolating or selecting multiple sequences from a nucleic 4° C. hold 1 acid sample by employing multiple unique selection probes in a single medium. Each selection probe has a sequence that 0374 PCR products in a single PCR plate were pooled is complementary to a unique target sequence that may be together. The seals of the PCR plates were pierced with a plate present in the sample under consideration. Single-stranded piercer and one pooling boat was placed on top of each PCR (e.g., denatured, double-stranded) selection probes anneal or plate. Each PCR plate-pooling boat assembly was inverted hybridize with sample sequences having the unique target and placed into the bucket of a table-top centrifuge. The PCR sequences specified by (e.g., complementary to) the selection plates were spun at 1000 rp.m. for one minute to transfer the probe sequences. Sequences from the sample that do not PCR product from the PCR plates to the pooling boats. The anneal or hybridize with the selection probes are separated PCR plate-pooling boat assemblies were removed from the from the bound sequences by an appropriate technique. The centrifuge and the assembly was Swirled to mix the contents bound sequences can then be freed to provide a mixture of of the pooling boats (i.e., the pooled PCR products from the US 2008/0280955 A1 Nov. 13, 2008 50

PCR plate). The pooled PCR products were decanted from target DNA) was immediately hybridized to oligonucleotide the pooling boat into a PCR pool tube, which was capped and microarrays or was stored at -20°C. set aside. The pooled PCR products were used immediately, 0379 All samples were hybridized to oligonucleotide or were stored at 4°C. (if the pooled PCR products were to be arrays (Affymetrix, Inc., Santa Clara, Calif.). For the samples stored for longer than one week, they were stored at -20°C. subjected to SPA, the final concentrations of the components 0375. After pooling, 125 ul of each pooled PCR product of the hybridization reaction cocktail was 3.0 MTMAC1, 10 was transferred to a 96-well PCR plate (now referred to as the mM Tris (pH 7.8 or 8.0), 0.01% Triton X-100, 0.05 nMb-948 “SAP plate”), which was subsequently sealed and spun down. control oligo, 3.7% formamide, 1663 ug/ml herring sperm The following was added to each aliquot of PCR product: 15 DNA, 92.59 g/ml antisense oligo, and 185.19 ug/ml labeled ul 10x One-Phor-All buffer (GE Healthcare) and 10 ul of 1 target in a total volume of 270 ul. For the PCR-amplified U/ul SAP (Promega Corporation), and the contents were samples, the final concentrations of the components of the mixed by pipetting up and down several times. The SAP hybridization reaction cocktail was 2.8 MTMAC1, 9.2 mM plates were sealed, placed into a thermocycler, and Subjected Tris(pH 7.8 or 8.0), 0.01% Triton X-100, 0.05 nM b-948 to incubation at 37° C. for 30 minutes followed by an 80° C. control oligo, 5.1% formamide, 365.04 ug/ml herring sperm incubation for 20 minutes. After the 80° C. incubation, the DNA, and 117.99 ug/ml labeled target in a total volume of SAP plates were held at 4°C. 271.2 ul. The contents were mixed by pipetting the solution 0376. The SAP-treated PCR products were purified using up and down several times. a vacuum filter apparatus. First, the entire contents of each 0380. The samples were hybridized to oligonucleotide well (150 ul) in the SAP plate was transferred to a separate microarrays referred to as “wafers” (Affymetrix, Inc., Santa well of a PALL ACROPREP3K vacuum filter plate (“purifi Clara, Calif.). Each wafer contains 49 arrays of oligonucle cation plate”). The empty wells of the purification plate were otide probes, each of which is equivalent to a single DNA chip sealed with a plastic Seal. The purification plate was placed on (Affymetrix, Inc., Santa Clara, Calif.). (In fact, chips may be top of a vacuum manifold and the vacuum manifold was manufactured by cutting arrays out of wafers and individually Switched on. It was ensured that the vacuum pressure read packaging them.) One hybridization reaction cocktail was >20 mm Hg. The vacuum was continued until all samples transferred into a first array on a wafer. This process was were dried. Once all samples were dried, the vacuum mani repeated for all other hybridization reaction cocktails. (That fold was switched off, and 40 ul of molecular biology-grade is, each array on a wafer received only one hybridization water was added to each well. The purification plate was reaction cocktail.) The wafers were incubated at 48°C. in a sealed incubated at room temperature for a minimum of 30 rotisserie incubator (“hybridization oven') where they were minutes on a flat surface, during which the plate was sub rotated at ~20 rp.m. overnight (-22-24 hours). jected to low-speed Vortexing for one minute every five min 0381. The wafers were retrieved from the rotisserie incu utes. Optionally, the plate was incubated overnight at 4°C. to bator, assembled into flow cells, and placed on a fluidics increase recovery of the DNA. The sample in a well was used station for staining. The wafers were rinsed with a solution of to wash the membrane in that well three times before the 1xMES and 0.01% Triton X-100 at room temperature prior to sample was transferred to a “purified DNA plate.” The puri staining. Three stain Solutions were used, and after each stain fied DNA plate was sealed with a plastic seal. The purified step the flow cells were drained and the wafers were rinsed PCR products were immediately quantified or stored at 4°C. with 1xMES and 0.01% Triton X-100; the stain steps and (if the purified PCR products were to be stored for longer than rinses took place at room temperature. The first stain Solution one week, they were stored at -20°C. applied to the wafers was 1xMES, 0.01% Triton X-100, 2.5 0377 The purified PCR products in the purified DNA mg/ml BSA, and 5ug/ml streptavidin. The second stain solu plates were quantified using optical density (OD) readings. tion applied to the wafers was 1xMES, 0.01% Triton X-100, First, 196 ul of MILLIPORE water was transferred to each 2.5 mg/ml BSA, and 1.25ug/mlbiotinylated anti-streptavidin well of a flat-bottomed clear GREINER 96-well OD plate antibody. The third stain solution applied to the wafers was ("quantification plate”). The purified DNA plate was vor 1xMES, 0.01% Triton X-100, 2.5 mg/ml BSA, and 1 g/ml texed and spun down at 1500 rp.m. using the SORVALL streptavidin-Cy-chrome. After staining and a final rinse with LEGEND centrifuge for 15 seconds. Four microliters of PCR 1xMES and 0.01% Triton X-100, the wafers were subjected product from each well of the purified DNA plates were to stringency washes. The wafers were washed twice with transferred to the corresponding location of the quantification 6xSSPE and 0.01% Triton X-100 at -37° C., followed by a plate. Both plates were sealed with CYCLE plate seals. The wash with 0.2XSSPE and 0.01% TritonX-100 at -37°C. with quantification plate was Vortexed for 10-15 seconds using the no intervening rinse with 1xMES and 0.01% Triton X-100. multi-tube vortexer and spun down for 15 seconds at 1500 The flow cells were then filled with 0.2xSSPE and placed in rp.m. using the SORVALL LEGEND centrifuge. The DNA a -37° C. convection oven for one hour. Finally, the 0.2x concentration was determined by measuring the OD of the SSPE was removed and the wafers were rinsed with 1xMES diluted samples in the quantification plate using a TECAN and 0.01% Triton X-100. After draining the flow cells they microplate reader according to the manufacturer's directions. were refilled with fresh 1XMES and 0.01% Triton X-100. 0378. The SAP-treated PCR products were labeled to After the wafers were stained and washed, they were removed allow detection after hybridization. Each well of a DNA label from the fluidics station, a back plate was added to the flow plate contained the following: 45 uM biotin mix (ddUTP/ cell assembly, and taken to the Scanner room for Scanning. dUTP) (Roche), 1x One-Phor-All buffer, 24. U?ul TaT (ter 0382. The laser was allowed to warm up for 15 minutes minal deoxynucleotidyl transferase: Roche), 32 ug SAP before scanning was initiated. The wafers were scanned with treated PCR product, and MILLIPORE water to a final the arc scanner, and if the images appeared to be out of focus volume of 50 ul. The reaction cocktail was mixed by pipetting or misaligned the scan the scanner was adjusted and the scan up and down several times, and the DNA label plate was restarted. Once all the wafers were scanned, any wafers that sealed with a plastic seal. The DNA label plate was placed were not successfully scanned were rescanned. If the scan into a thermocycler and was held at 37° C. for 90 minutes, was successful, the DAT files were submitted to the database. heated to 99° C. for 10 minutes, and then cooled and held at The wafers were removed from the scanner platform, and 4°C. After labeling, the labeled PCR products (i.e., “labeled stored in a refrigerator at 4°C. until no longer needed. The US 2008/0280955 A1 Nov. 13, 2008 51

DAT files were analyzed to determine the genotypes of each used to phase the genotype data (i.e., to determine which individual at each SNP location, and the allele frequencies in allele of each SNP is on which chromosome). Haplotype the case group (those who exhibited edema) were compared allele frequencies obtained from haplotype samplings were to those of the control group to determine SNPs and haplotype used for association tests to avoid problems related to using patterns associated with an increased incidence of edema in haplotypes resulting from maximum likelihood estimates. response to thiazolidinedione therapy (see U.S. patent appli The haplotype trend regression test (Zaykin, D. V., Westfall, P. H. Young, S. S. Karnoub. M. C. Wagner, M.J., Ehm, M. cation Ser. No. 10/970,761, filed Oct. 20, 2004, entitled G. (2002). Testing association of statistically inferred haplo Analysis Methods and Apparatus for Individual Genotyp types with discrete and continuous traits in Samples of unre ing,” and U.S. patent application Ser. No. 11/173,809, filed lated individuals. Human Heredity 53, 79-91) was performed Jul. 1, 2005, entitled “Algorithm for Estimating Accuracy of for all haplotype sliding windows of sizes 1 through 9, while Genotype Assignment.” ignoring haplotype alleles with very low frequencies (<5%). 0383 Tests for association of SNP genotypes with edema Permutations of the phenotypes were carried out to adjust were based on logistic regressions of edema status on geno estimates of significance for the number of tests performed. type under a multiplicative risk model, with the inclusion of 0386 Haplotype analyses were first done on an interme principal components that represent population structure diate data set of 364 edema cases and 751 controls. One (Price, A. L., Patterson, N.J., Plenge, R. M., et al (2006) significantly associated (p-value=1.1x10) six-SNP haplo Principal components analysis corrects for stratification in type was identified on chromosome 14 (genes: SERPINA10 genome-wide association studies. Nature Genetics 38,904 and SERPINA6) with a haplotype frequency of 7.2%. This 909) as covariates. A total of 345 SNPs were identified that same haplotype when tested for association on the remaining yielded a p-value <0.001 in the association analysis of edema samples (278 edema cases and 925 controls) yielded a p-value against SNP genotype, and these SNPs are provided in Tables of 0.029 and relative risk of ~1.4. The haplotype frequency 9-11, as described above. For each SNP, identifiers are pro was 6.8% in the second sample set. Three of the 6 SNPs in the vided (rsID and ssID in the NCBIdbSNP database (ncbi.nlm. associated haplotype are nonsynonymous SNPs in SER nih.gov/projectS/SNP)), as are locations on the human PINA10 (Table 12.) genome (NCBI Build 35). Also provided are allele frequen (0387 SERPINA10 (serpin peptidase inhibitor, clade A, cies within cases and controls, estimated odds ratios, map member 10) encodes a protein that inhibits the activated pings of SNPs to genes and p-values for association tests. coagulation factors X and XI. Nonsense mutation in this gene 0384 The heterozygous odds ratio is defined as the odds are associated with venous thrombosis. SERPINA6 (serpin of edema in persons with one copy of the predisposing allele peptidase inhibitor, clade A, member 6) encodes a protein (“associated allele) divided by the odds of edema in persons with corticosteroid-binding properties and may be an indica with no copies of the predisposing allele. For rare traits, the tor for both insulin resistance and low grade inflammation. heterozygous odds ratio is closely related to the heterozygous 0388. The six-SNP haplotype may be used along with the relative risk, which is the ratio of the risk of presenting the other significantly-associated SNPs (Tables 9-11), for trait in persons with one copy of the predisposing allele to the example, to develop diagnostics (e.g., in vitro diagnostic mul risk in persons with no copies of the predisposing allele. tivariate index assay, or “IVDMIA) for identification of indi Logistic regression is a tool for association analysis from viduals who are predisposed to edema in response to thiazo which odds ratios were estimated, under a multiplicative lidinedionetherapy, or to further study the biological basis for model of genetic risk; an analysis of deviance of the edema drug response. trait, adjusting for principal components that represent popu (0389. While preferred embodiments of the present inven lation structure and experimental variability, was used to esti tion have been shown and described herein, it will be obvious mate the significance of the association. The p-value is the to those skilled in the art that such embodiments are provided likelihood that the deviance attributable to SNP genotypes by way of example only. Numerous variations, changes, and would be as extreme as the observed deviance in the absence substitutions will now occur to those skilled in the art without of a true association between the genotype and edema. departing from the invention. It should be understood that 0385) A haplotype analysis was also completed to dis various alternatives to the embodiments of the invention cover haplotype patterns potentially associated with edema. described herein may be employed in practicing the inven The fastPHASE program (Scheet, P., Stephens, M. (2006) A tion. It is intended that the following claims define the scope fast and flexible statistical model for large-scale population of the invention and that methods and structures within the genotype data: Applications to inferring missing genotypes Scope of these claims and their equivalents be covered and haplotypic phase. Am J Hum Genet 78, 629-644) was thereby.

TABLE 9

SNP information (Chromosome, Accession and Position in Human Genome, NCBI Build 35; rSID and SSID in NCBI doSNP database

rsD ss ID Chr Accession Position Assayed Sequence

234 24 431570 7 NCOOOOOf 11 1 O5155O86 GGCAGAGACTGAATNAAGGGTTGACCCAG

4 OOf 23498869 11 NCOOOO11.8 33844118 CAGACCTTCTTC CANCTGTAAAATTCCCA

324 O1. 2344 6086 5 NCOOOOO5.8 1672791.87 AAGAGGTAACCCCTNGACCTAAGAGGAAA

163299 23.975386 5 NCOOOOO5.8 782241.71 ATTTCTTGAGAAGTNCAACAACACAGTGA

1796 60 24 O834. Os 14 NCOOOO14.7 3O398.905 CAAAATTTGCTTAGNTAACTTCCCCGGGG US 2008/0280955 A1 Nov. 13, 2008 52

TABLE 9- continued

SNP information (Chromosome Accession and Position in Human Genome, NCBI Build 35; rSID and SSID in NCBI dbSNP database)

rs ID sSID Chr Accession Position Assayed Sequence

197894 24O45715 NCOOOO 9 95.631.109 AGATTTGAGAAAAGNTTCAAAATGCAAAT

247 O52 245.37584 16 NCOOOO 16. 8 56524719 TAGTGTGTGCTACTNCCTATTTGGATAAC

261712 23831.465 NCOOOO 23. 8 1177715.08 GCTAGTAGATTTCANGTCTATTAACAGTC

399.516 24 684.478 NCOOOO O6. 9 14.58525.42 CTTGCTCTCTAATCNTCAGCATCTTCGTG

478,239 24225486 NCOOOO 9. 8 TAGAATGCACAAATNAGCATAAAAGAAAA

489977 24512768 NCOOOO ... 8 368 45848 AAATATGAATAATTNTTTGACCAGTACTT

51097 O 2452O470 NCOOOO 9 14 O99.456 ACCATAAAAAGACANTTCTCAGCAGAGAC

518497 24 OO2359 NCOOOO 2. 1125.655O2 GGCAATGAGGCTTANGTATTTGTGTTTCT

244.31617 NCOOOO 9 12821669 ATGCTCAACAGCCANTAAGATCTTTCAGA

579596 24 67.4812 NCOOOO 8. 8 32O37 O28 AAATGCACATGGATNGTTTTGACCACAGC

622.946 2416721 O NCOOOO 9 313 O4592 CCGTTTGACAAGGTNTCTGGCTGATATAA

658812 23.513.964 NCOOOO ... 8 6503. O515 TAAGAAGCATTGATNCAGGAAATATCTTA

7 O3406 23608,899 NCOOOO ... 8 1194.29569 CCAGGCAATTCATCNTGTCTCAAGGCAGA

713286 23356 479 NCOOOO O8. 9 92 O914.5 AATGAGAGCTTGTANATAAAAGTCCTTGC

24476902 NCOOOO O. 8 4.9426368 TTCTGCAACCTGCTNCAACCAGGACTCTT

855965 236 O8911 NCOOOO ... 8 1194,33749 CTGGCTCCCCGCTCNATGGTTTTCAGCTG

8.71962 24.296 O57 NCOOOO O3. 9 15 OO 61313 TGAGGGTGAAATTTNGAGAGCTGAGGAAA

882685 243 05633 NCOOOO O2. 9 2114 O5508 TTAAGGCAGTGCCCNAACTTTTATCTATT

886 126 233 89735 NCOOOO 12. 11 O141934 AGCCCAATAGTCTGNAGTTTGTCCAGAAG

888784 23247790 NCOOOO 8 1686.3288O GCCAAGTTTCTACCNGAGGCTTGGCTTCC

891.978 23.753. Of 6 NCOOOO 8 TAGACTTTGGAGCCNATTTTCTTCTTTCA

9 O2271 24189394 NCOOOO 15. 8 27023816 CATCCTCTATTTTGNACGCTCAGTCACCC

9 O3346 246 42.423 NCOOOO O3. 9 273 SOS21 AACACCTGTACACANAACTGCAGGGCCCT

96.2521 233 67125 NCOOOO 11 14174 6776 GTAAGAATGTCTTCNTTACAGAATAATGC

9 67702 244 585.45 NCOOOO 5. 8 35746 OO 9 TCTGCTATTACCAGNACTCTTCAGTATTA

O12968 23.5776.36 NCOOOO 9 107988 754 TTCACTTTAGAAATNAATGGATTATTAGT

O17672 2466 6309 NCOOOO 9. Of 82428 TCTGGCCATCCCTGNCTGGAACCTGTTCT

O25623 24 65O193 NCOOOO 31298.139 TTAGCATACGTTTTNTAATAATTATGTTA

24O92882 NCOOOO 1332.1288 TAAATGTGGGACCTNAGATTTGAACCCTA

Of 6184. 245.79881 NCOOOO 32O16863 AGAATGAGTTCTTTNTGCAGTTCCATTGG

23552724 NCOOOO 72.878596 AGATGATTTAGGCTNAGAAAGAGGAGGCC

106449 239 61108 NCOOOO 8 17355O 629 GATCGATATCTGTANTTTGACTTTCTTAT

106722 23.792505 NCOOOO 4. 7 62.3972.99 CTGTCTTAGGCACTNAGCCACAATCTCAA

13O866 24 652879 NCOOOO O2. 858 O5399 TTGCAGCCCTCACANTCTGGTTCTGGAAG

137895 NCOOOO 9. 8 556.23776 GTGAGGCCTGGGACNTTTTTAAGATCGCT US 2008/0280955 A1 Nov. 13, 2008 53

TAB LE 9- continued

SNP information (Chromosome Accession and Position in Human Genome, NCBI Build 35; rSID and SSID in NCBI dbSNP database)

rs ID sSID Chr Accession Position Assayed Sequence

144963 241.375.93 12 NCOOOO12. 9 67621,892 ACCCCCAGCAAAACNGGATTTGTTTGTTT

156822 238 68266 NCOOOOO2. 9 41736.479 CTAAAATCTACTTTNATATTTCTCAGCCT

161098 247 Of 116 12 NCOOOO12. 661.33727 ATTTTGACTGGCGCNGCAGAATGAGGAGG

194586 24284.512 NCOOOOO1. 15113O491 TCTCCTGGAAAGACNGGCTCTCTCAGGTT

261166 23938179 12 NCOOOO12. 321-34 651 CGTGACTTATAATTNGTAGACACTCAGTG

3 41513 245 O3921. 13 NCOOOO13. 69785536 TTTATTTTCACCCANAAATTTACATAGAA

3 48994 236.88892 NCOOOOO3. 11 OO37.946 TGTTTTCAATGTTTNTGCTGATTTTTTTC

35.4444 2324 O905 NCOOOOO3. 15504 OO58 CTTCTGGAATATCANTGAATCTTGAATGT

361933 24.6958O4 NCOOOO2 O. 45.9 O2724 TACCTTATCCCCATNGAGACGTCGCTGGA

369905 24345 666 NCOOOOO3. 1O 6154941 CTATAAGGCCGTACNTTGTCTCCTTTCAT

370116 24159111 NCOOOOO3. 211.87137 TAGTTATGACTTCANACCAAAATATTACT

389 173 23354 O97 NCOOOOO4. 285 O3381 TATGTCATACCATTNATCGTGATGCTCAA

437937 23914.146 NCOOOOO2. 15 O576382 AATATGAGACATCANAATACAGAGAATGA

45O 631 23.4355.75 NCOOOOO5. 1658 60873 TGCTCTAATTTCCCNATGTCGGTTACTAT

4528 Of 24.545243 NCOOOOO8. 782.51054 CTTACAAGGCCAGCNATATAGGCAGCCAT

4724.24 2318.3508 NCOOOOO4. 83 O92653 GTACAGTACTGTTTNGAAGGTTTTATGCT

482674 234.11034 NCOOOOO5. 44404 OOf AATTCAATCAGAGTNCCAGTCACTAATAA

24290.135 NCOOOOO3. 3938 O35 ATTTCTAAGCTCTANGTAGGTGAAATCCC

5 OOO65 2373O828 NCOOOO12. 33O82138 CAGGTTTATTATTANAAAAGTCAGTTGTT

5. OfS99 2355.2695 NCOOOOO7. 11 858 66910 TTATGACCATGTGANTAACAAAAATTCTG

5.24 408 24 673906 NCOOOOO7. 11 54 OOO446 TAAAACTATAACACNCAGTTTCCAGAGCA

5.43976 24 627613 NCOOOOO2. 3390485.8 TTAGGGTTAGTTGTNACAGATTGCTCAGT

58.4769 24. Of 48.33 NCOOOO O. 8 13 O845591 TCAAATTGAAGTTTNAATTGG AAATGGG

663,588 241.3758O NCOOOO 675 63432 GCGGCATGGGGAGGNCAGAATAGATAAGG

671413 24410446 NCOOOO O8. 1327 O959 GATTGCCTCAGCCTNTGATGA GTTTAGA

745836 2443.1150 NCOOOO 3. 462.35847 AATATTTGCAGGATNGTCTTAGAATTCAT

748952 24 6 O386.5 NCOOOO 95.221,437 CAGGGAGTTCTTCANAAGTGG TATCCTA

798.255 233,2895.3 NCOOOO 32178526 GGGAGGCAAGTGTGNTAGTCCAAGTAAAA

831369 24.171766 NCOOOO 9 122395 O96 CAGACTTCCTCCTTNTAGGAC CTCTGAG

862.505 24.217412 NCOOOO 265 684 O3 AGTGTGATCTGAATNTTTGGG ATCCTTC

876533 239 Ofsf O NCOOOO O4. 77574991 TAGCAGATAATGTTNAAATTAAGGAATGA

880 692 2433 6.556 NCOOOO 1. 8 OO15717 AAAGGCCATTTGTTNTTGGGTGTAACAAT

9 OS325 24422327 NCOOOO 83.393.793. GGAGGCATCATACANCCTGACTTAGAAAT

93,5153 245 688O6 NCOOOO 72580474 TGAAGTCAGAGTCANGAGGGCCAGCTGCA

9 893 OS 23887548 NCOOOO O4. 2223 7615 AATTTTCAACTCATNTGAAAACATGATGA US 2008/0280955 A1 Nov. 13, 2008 54

TAB LE 9- continued

SNP information (Chromosome, Accession and Position in Human Genome, NCBI Build 35; rsID and SSID in NCBI dbSNP database)

rs ID sSID Chr Accession Position Assayed Sequence

2008 O58 242O6129 20 NCOOOO2O. 9 491OO42 CAATTACTATTGGCNGTATCTTTCTCTTT

2O107.11 243 OO319 4. NCOOOOO4. 222 O9776 AGACAATACATGAANGAATGCAACTGTGT

2O25122 24417281 NCOOOOO 6. 91.7898 CTGTCCTCCCCACCNCACTGTAAGTTCTT

243. Of 687 NCOOOOO3. 87O694.73 AAAAAATAACCACANTGCCACCAAAATAT

2O34796 24345729 NCOOOOO4. 14789147 TGGCTTCCGGGCTANTGAATTTAATTTGA

2O37293 2473O486 NCOOOO23. 333 69292 TACCCCTTAGCTTANAAGCAAAAAAGAAA

2O61717 24328 O26 NCOOOOO5. 8 101.33 6908 TTGAGGAATGTACANATTTTATTCTGTTG

2O731.45 24451923 NCOOOO2 O. 9 55624 O4 OTTGCTGGGGCCTCTNGGCTGCAGAAAGAA

2O781.31 235.45887 18 NCOOOO18. 44615 OO ATATGCCCAATCTANTCTGACCTTCACCC

2119099 245 64.146 NCOOOO1 O. 13 O1083 O CATCTCTCCAAAGANGCTCAGGTCTCCGT

2148 694 24 Of2811 NCOOOO2 O. 53214464 CTTTGATAATTTGGNGTCTTAGTTTGTTT

22 17368 24 6299.13 NCOOOOO2. 83626483 AAAATCAGTGGGCCNGATACTAGAGATAG

224 O142 23475.360 16 NCOOOO16. 2752 648 TCCCGCAGTAGAAGNTTAGTTAGACGTGG

227 O927 241891.33 NCOOOOO5. 75627466 ATATGCAAATTTCANTATTAACTTTACAA

227.7594 241-26822 15 NCOOOO15. 996.80 410 GGCAAGCAGGCCCCNGGCATTTCAAAGCG

22 77937 24 O22954 NCOOOOO5. 13779.358 TCCTCTGAGCACTCNGGCATTTGTCATTG

22 78381 23935144 NCOOOOO5. 1468 OS 542 GTTCAGGGCTCTTTNTATACCTGAGGCCT

2281628 24 O995O2 NCOOOO14. 33059 62.5 TTTCAGGAATAAAANCAACACAATTATTT

2285 646 235.49839 NCOOOOO7. 87119089 CCCTGACCAAAAAANAAAAGATTTTTCAT

2351325 23458376 NCOOOOO8. 111912O18 TGTTATATACTAGANTTTGATAGCTATTA

2375592 24 6843 O1 19 NCOOOO19. 17494933 GCCTTGAAAGCACCNGAGAGTCTAGTCTC

2388 O62 23321 O6 O 12 NCOOOO12. 3758.9369 TTATATATCTTTCCNTTTATTTAGGTCTT

24 12711 2396O 627 15 NCOOOO15. 4 O484523 CTCAATTGACATTTNGCTCCAGTGTCGAG

2418978 24524 819 NCOOOO10. 109s 11663 TTATCTAAATTCTGNTCTTCACTCAATAT

24.26778 23452.529 NCOOOO2 O. 56,726.884 GTTCCGGGAAGTCCNTCTCCAGCAGGAAC

2437 095 23374778 NCOOOOO6. 1297.6982 GCAGCACCCTGTATNTGATATTAATATTT

24.772O2 231736.33 NCOOOOO1. 178978146 TTCTTTCAGCCCTGNTCTCTAAAGGATGG

255062 O 24.195.805 16 NCOOOO16. 7723 OO99 CACTTCAGATTCCANTCGAATACATTAGA

2550621 241958O6 16 NCOOOO16. 772.33 O32 GCAGATGCCCGGCTNGTGGTTAACCCAAG

2579875 23534378 NCOOOOO8. 13 O490615 GCCGCATCTCTGATNTCAGAGCATTTACA

2664538 23574543 NCOOOO2 O. 44 Of3 632 AGGACTCTACACCCNGGACGGCAATGCTG

26.82968 24.2783O4. NCOOOOO3. 6. Os 6164 AGCTCCTACATGTCNTTTTGAGACCTTAT

27 O4789 24166412 NCOOOOO2. 1463 47039 ACGTGATTACAAATNGGGAAAAGAGGGGC

2714 678 23531563 NCOOOOO7. 11 789.38528 TATACACACAGAAANAAATACTGGTGAGA

27385.91 24195821 16 NCOOOO16. 8 77239356 AAATTTCATATGAANGGTGGGCTTTTCTT US 2008/0280955 A1 Nov. 13, 2008 55

TAB LE 9- continued

SNP information (Chromosome Accession and Position in Human Genome, NCBI Build 35; rSID and SSID in NCBI dbSNP database)

rs ID sSID Chr Accession Position Assayed Sequence

2764951 231991-94 NCOOOOO1. 8 212.495364 AACTGAAGATTCCCNTTTATTTTTCTCCA

2825163 242O5434 21 NCOOOO21. 7 1911-1893 CATTATCACAAAACNTAATACCTGAAGAT

2851.391 2455.1945 21 NCOOOO21. 7 4336O473 AACCTGACCCTCGGNGTGTCTGTCTGTAA

291.01.04 241. Offs2 12 NCOOOO12. 6.738.8296 TTCAGTTAGTCTAANTTATGAGGATATAT

2991.345 2383,719 O NCOOOOO1. 8 4163842O ATGGCTCTTCGTCCNATGATTCTAAAGCC

31.17888 2333 4891 NCOOOOO9. 9 108.107382 AAAAGAATTTTTAGNTCCTATGTCATAGT

3732 768 23673768 NCOOOOO3. 9 1525.95266 CATGCAATCACATCNCAGCAGCAGTTGAT

37416O1 24. 441058 12 NCOOOO12. 674 61289 GGCAAAGTATTTGTNATTAGGAATATCTG

3746229 23631 O96 19 NCOOOO19. 8 624 65914 GCAGGCTTAGTCACNTTGATGGATCTGTC

3775561 24 662115 NCOOOOO4. 9 18572.8296 GGCTTTTAAAGTTCNCACAGACAGGCATC

37.81575 234988OO 11 NCOOOO11. 3384 1895 CCTGTCTTACTTGGNGTTGTCGAGTTCCT

3795.294 236 68 OO4 NCOOOOO1. 23 4894.62 ACTATATAGACAAANGCATGAGAGCACAA

38221.96 24372.212 NCOOOOO4. 684 43565 CATTATTTATCATCNTCAACATTATTGCT

382,7896 23654688 NCOOOO14. 9.3831174. TAAAGGAAGGCAGCNGAGTATATTGGGAA

3844 O55 231883.49 NCOOOOO1. 64231244 GCATGAGTACAAGCNGAGGTTCACATACC

385O225 24 654763 NCOOOOO 6. 9 143 Off 620 ACACAATTCTTAATNTTTGGATCAGGCAT

4O76941 238102O2 11 NCOOOO11. 11218 143 CCATTATCACCTTANTTACAGCAATCTCT

414 Of 68 24704 O28 12 NCOOOO12. 150 02771 TGCCCAACGTGTGANGTCATGCCACCAAG

41424.36 23375.459 NCOOOOO9. 14442OO ATATCTTTCCTTTGNATCAAACAGAACAG

43 O5582 2371413 O NCOOOOO4. 57869929 TTGCTCAAATAAACNGTTAATTTGTCTAA

43.45821 238,53978 NCOOOOO1. 84 61999.1 TCAGCTGCTGAAGCNACTGAATTACAATG

43.96895 2433292.8 NCOOOOO3. 8664 6876 AGATTGTGTCTTCANTGTTAAATTAGATA

4397143 23258.338 NCOOOOO5. 8 1767 O9 628 GACTGGAGATGCACNAGGGGCCAGATTGT

4398609 2435681.1 NCOOOOO5. 8 101.316 787 TGTTGGGGTGTCTANCAATAGGGCCTGAT

4439342 238731.63 NCOOOOO1. 8 1927.347.7 CAACATGCTGATTANTCAAGTTAACACCT

4461 OO9 24224897 15 NCOOOO15. 8 575899 OO ACATTCCAGTAGAANAAGTAAAAAGCCAA

44.65511. 2339.95.79 13 NCOOOO13. 9 4 O852457 AGATAAAGCAGACANCAACAAAGCAGAGA

4565762 23655.425 NCOOOOO1. 8 4905052O AGCCATAAAAAGAGNGTACGCCAACCCCC

469 OOO1 23891796 NCOOOOO4. 9 291.2146 CTTAATCTTGATTANTGGGCTCAGAATGT

469.91.97 2323.7336 NCOOOOO4. 9 106.9995.27 CTATTACCAAGTTCNGTCATTAGAGCAGT

24418999 NCOOOOO 6. 9 88.882O61 AAAACAGCATGGGCNCAGGCCAGTTCAAA.

47 O9984 241.46213 NCOOOOO 6. 9 1661.66746 AATCAGATTTCAAANCTCCAGTTCCATTT

4718891 2444 O338 NCOOOOO7. 11 6835.1912 ACTCAGCTTCCTATNTGTTTTTGTAAGCC

474 61.36 241-1904 O NCOOOO1 O. 8 74971 OOO AAGCACGGGTATCTNTACACAAATAAGTT

47 91962 24592 O48 17 NCOOOO17. 9 101 O9505 ATGAACTCATCTATNTTTTTATACTCTAC US 2008/0280955 A1 Nov. 13, 2008 56

TAB LE 9- continued

SNP information (Chromosome Accession and Position in Human Genome, NCBI Build 35; rSID and SSID in NCBI dbSNP database)

rs ID sSID Chr Accession Position Assayed Sequence

4845963 23843186 NCOOOOO1. 8 109 O53.54 CAGAGCACAGGGAGNACCTGCGGCTTTTA

48.59897 2316 O853 NCOOOOO4. 9 79.277 659 TCCCAATAGAAATGNTTGAAAATATGAAA

4876347 24.1994 O6 NCOOOOO8. 9 112O62315 GTGACAACCCTTTANGCTGTGGTAACAAA

4943 826 233 O2101 NCOOOO11. 8 8073. O697 TGTAACTGGCTGAANTGAAATTGACTACA

4973 848 2327449 O NCOOOOO3. 9 27O 4343 O CTCATGTTGGATCTNCCTCAAGGCATTCC

49764 O1 23739713 NCOOOOO5. 8 136,439 Of2 AAGGGCCAAGTGATNCAGGTTTTCCAGAA

4976685 23258293 NCOOOOO5. 8 176698783 TCTGCTCTGCCTTCNGTACTTCCCGCGGC

49822O7 24578. O93 14 NCOOOO14. TTCTCGTTATTGGGNCACAAGAAAAAGCA

4982 689 2472O936 14 NCOOOO14. 7 22391,199 TACCAGTGGTAGTTNTGATTACATAAGTA

59 10439 247294 68 NCOOOO23. 8 11782O679 ATGTAGCCAATTTGNTGTTAAAAAAATAG

595708O 24.723 435 NCOOOO23. 8 11785.353 O GGGACTGTTTTTCCNCAAAGGTTTATCTT

598O169 238164.57 NCOOOO23. 8 75.91549 GTCCTTTCTGACTGNCAGGTGTTATACAA

5.992689 23787 O11 22 NCOOOO22. 8 16274.395 TTTAATGTTTATCCNTATGCATTTATCAC

6070619 245.98466 NCOOOO2 O. 9 56816552 AGCCGTGTCATTAGNATGCGTCTTAGAAT

6444. O52 24 6418O1 NCOOOOO3. 9 1865 45142 CCAACACAGAGTACNGCCTTAATCGTATT

646933 O 24 O17213 NCOOOOO8. 9 11.198O132 AATTGTTGCATGTTNTCCATCAGTAGTAA

648.1643 24 624 O89 NCOOOO1 O. 8 3 O178417 GCTCAAATTGGAGANAGACTATCCTATAG

656.31.27 24453. 495 13 NCOOOO13. 9 79114148 AGAATAGGCAAACANTGAATGCAATATTG

65.74271 24.134154 14 NCOOOO14. 7 7565.0408 CCAGTTGTTTGGGCNCTCATCTGGGAAGC

65.962OO 24356.774 NCOOOOO5. 8 O13 O1550 TTGCCAAGGCCGATNTTGAGAGGATATTT

6681627 24.276577 NCOOOOO1. 8 7 OS 58.399 ATCACCTTAATTGTNTTTTATCTAGGTTC

6698 O91 242 573.47 NCOOOOO1. 8 384 O596.7 TAATTCGAGGCTGTNGGGCTGAGGACCCT

67. Of 185 231821.25 NCOOOOO2. 9 27O63258 ATCTGACTTTAAAANTTAAAAAGACAATT

672558 O 24 63 4209 NCOOOOO2. 9 836235.89 TTATTTGATACCGANATAGGCAATTTTAA

67.66574 232894 63 NCOOOOO3. 9 88173.316 TCCCCTTAGGAGCANGTGGGAAGAAGAGG

677742 24282737 NCOOOOO3. 9 69.856688 AGGGTCTCTGTAGCNGGAACTCTCAGGTC

6813595 24 63 Offe NCOOOOO4. 9 54334.392 ATAAGTTCTTCCAGNCCAGGATGGCTTTC

686 OO1 O 23324332 NCOOOOO5. 8 26679.348 AATATTGTGAAACANTCTGAGCGCAAAAT

68 6694. O 237.58509 NCOOOOO5. 8 29125537 CAGTGTTCTAACTCNTAAGTGGGAGCTGA

6897 128 24188971 NCOOOOO5. 8 75489276 ACTCTAGTGGTAACNAATTCACATAAACA

6921677 243.73 670 NCOOOOO 6. 9 162O6923 ATTTGGCAGTCTTGNGAGTCAAAAGCATA

6941698 24 684. 483 NCOOOOO 6. 9. 145856838 CATAGAATAAGTTANGGAGCAGTCCCTCT

69 62.459 24 6752O3 NCOOOOO7. 11 5SO 80681 ATCTAGAAGGAAATNGGACTTTTTAATAT

6968 649 234.33229 NCOOOOO7. 11 16369925 AGAAATATTGTCAGNGCAAAAGGGCTAGG

6969 869 243 82.469 NCOOOOO7. 11 16899639 ATTATAAGATTGCTNGGATAAAACAAAGT US 2008/0280955 A1 Nov. 13, 2008 57

TABLE 9- continued

SNP information (Chromosome Accession and Position in Human Genome, NCBI Build 35; rSID and SSID in NCBI dbSNP database)

rs ID sSID Chr Accession Position Assayed Sequence

7 OO2174 24 O841.38 NCOOOO 9 78.188119 AATTGCGTTTCTTTNATGATAAATCAATT

7121669 11 NCOOOO 11. 33.836123 CGTCGGGACCCTCCNGGGCTAGCGCGCTT

717734. O 23544.375 15 NCOOOO 15. 783 49914 CCTAGGGTCTATGGNTTTTGTTGCCATTG

725.7225 24 6821.33 19 NCOOOO 19. 372671.78 TGCAGAGAGATACANACGAATGCCCAGCT

73281. Of 239.83332 13 NCOOOO 13. 44379 639 GGAGCAGTGGAAGCNTAGGTATTCTCTTC

742.91.19 23755.325 NCOOOO O3. 1864.84 O13 ACCTGTTTCTGGCTNCCCGGCAGAACCTC

742.95.09 23673764 NCOOOO O3. 15258.3865 TGGTATTATGATAGNAGGCTTAGATTCAA

744928O NCOOOO 34513495 TTATGTCACAGGGGNTTAGAGGACACAGG

7s 2479 24.257106 NCOOOO O1. 68O31,561 CCTGAGTTATCCATNGACAAGAGAATGAG

23255 656 NCOOOO O2. 1537.1789 O TCAAAGGGCAACTTNCTTAAAGCATTTTT

7587 O23 233 O1107 NCOOOO O2. 150 60921 CAATTTCATATGCANCCCATGTGAGCTTT

7631594 241-34893 NCOOOO O3. GAATTCATGATCCANGTAATAGTACTAAA

7632,294 2434.2534 NCOOOO O3. 157833 085 TAAAATTCAGATTCNGGGCCTGCCGTGGT

7635.836 23275,312 NCOOOO O3. 27116122 AGGTGCCTTGCACANTGCGTACCACATAG

765.7964 246455.87 NCOOOO O4. 9 5584,399 GTGAATGAACGAATNATGATGGCCAACAG

7666.299 2423. 6069 NCOOOO O4. 9 84 O12513 AAGCCGAAGGATGCNGAAATGTGGCACTG

f6 68673 243.98923 NCOOOO O4. 9 CGGTATGTTGCAAGNGGAAGTACTTTTTC

767 OO13 23742709 NCOOOO O4. 9 16995272 O CACATTAATTCCTGNGTAAGAAAATTATA

244973 O1 NCOOOO O6. 8 OOOffs 6 TGCTGTGTTTTACCNATGCAAATGCTGGA

78O2597 23534456 NCOOOO 11 11568272 CCAAGAACCCCATTNTGAAGTTGTCCTAG

78. Of 431 233.51577 NCOOOO 11 70439 O26 TTTGGCCCGATGGGNGTATGGATAAATTC

7832O77 NCOOOO O8. 8095,824 O CCCCTTTAGCCAAANTGCACTTAGGATAA

7845273 23589 693 NCOOOO O8. 8 O945.459 TTAAGAATAGTTGANATGGCAATTATGAA

7855874 243. OS257 NCOOOO 285 62O86 TGGATATAAACTCTNTTCTTGGCATGTAA

79 095.16 23.385 O28 NCOOOO O. 77.555.343 CAGAGTAAAATTGCNTACCATCTGTCAAG

794.2997 23623726 NCOOOO 949.35943 GTTAGTCTGTATTANGAAAGGGGACTGAA

796.4255 2379.71.69 NCOOOO 92.288 OO2 ATCATCATCTCTATNCACACTGGGAATTA

79692.24 24428 656 NCOOOO 84592,343 GGTAGAACCATAGANTGTAAGTATCAGTT

8O1114 O 245.72712 NCOOOO 9928O123 CCAGTTGCTGAGGTNGGTAAAAGGTCGCC

8O24294 23743 OO 9 NCOOOO 91.8241.36 TTATCAGTACACAANCAGGTCACCTGACT

8O32896 24523 605 NCOOOO 78.3581.61 AGGCCCAGGGAATANGCTGCCCAAAGTGA

8O804. 6 O 247 O5581 NCOOOO 66980486 TATGAACTCCCTTANAGTAGGTGGGTGCA

8091.352 234.79883 NCOOOO 135 068O2 AGGAGAGTGGCCTTNTATCAGCCTGTGTT

81 03560 24225485 NCOOOO 5.991869 GTTCTGTATCTTGANGGTGGTATTGTTAC

8108576 23631 O18 NCOOOO 62450 419 AGTCTTTAAATATTNTAATGGTTCGTGAA US 2008/0280955 A1 Nov. 13, 2008 58

TAB LE 9- continued

SNP information (Chromosome Accession and Position in Human Genome, NCBI Build 35; rsID and SSID in NCBI dbSNP database)

rs ID sSID Chr Accession Position Assayed Sequence

93 OO16O 24 OO1822 12 NCOOOO12. 23672817 TGTTCACTTTCTTCNTTCAAGGAGCAGTT

93 O6955 24 65133 O 4. NCOOOOO4. 37.793 416 AAGACATATCATTCNCACTATAATTCCAA

9314751. 23431,158 9 NCOOOOO9. 861294.23 CAGCACTTTACAAGNTTCAGAAAACTCCA

936.735923768890 6 NCOOOOO 6. 496 O22OO ACCTGAGTGTTGCCNATGCGGATCTACTC

93.955 O4 24 68.7509 6 NCOOOOO 6. 496 O2892 AGGAGAAATTACTGNATGAGAACAAATGA

95.433 83 2452O751 13 NCOOOO13. 7295.3806 TCCATCTACGCACANTAAAAAGGCATTAT

95.74385 23971,198 13 NCOOOO13. 7873O24 AACTAGTATGTTTANTCTATTTTTCTTTA

97.256.95 23186933 NCOOOOO1. 8 22164762O TACAAGGAAGTTAANATC TAGAGCGATCA

98091732327497 O 3 NCOOOOO3. 9 27 OS 6229 CTCCCTCTGTGTAANTTCCTTGGAATACA

982 666.224296 O64 NCOOOOO3. 9 15 OO 61426 GTCTAAGAACAATGNAAA CCATTGAAGA

98.31663. 232.24 477 3 NCOOOOO3. 9 39.35462 ATTTGTAGTTTTGCNGATAAAGAACACTT

9 89365.1241.21997 17 NCOOOO17. 1 O1266.97 CCAATAAGTTCATCNGTG TCTAAACTAT

99.9621.8 23160392 NCOOOOO4. 791076.79 GTATCTTTGTTCACNTTGT TCATGGCTTC

1 OO11864.2391425 O NCOOOOO4. 3.1933142 CTTTTTAAAAATCANCCT TAAGATTGCCA

OO5763O 23410686 NCOOOOO5. 443 63 621 AGCACAAATTCTTTNCTG ATGTGGAGAC

O113 434 24 O88899 NCOOOOO8. 9 112OO4972 GAATCTATAAATTCNGCT CATGTCATGA

O17339823 696 624 NCOOOOO2. 9 15318OsO2. CTTTATATTATCTGNGTTGTCAGTTTTTA

O1854. 7123246611 NCOOOOO2. 9 18 O5351.12 TCATAACTCTCTCGNGAG GATAACATCT

O234 682 24392.434 NCOOOOO7. 11 21881299 GGGAACCTTGAGGGNAGGATAAGTTGAAT

O2347 O2 24.3924.36 NCOOOOO7. 11 218813 61 GAGGTGGGAGAGGANCTT CCATTTTAGA

O2698 OS 24 4294.91 NCOOOOO7. 11 16837773 TTACATTCTAACTANCCT CAAGATCCAA

O269951 2438866 O NCOOOOO7. 11 2O879 159 AAACATCCGGAAGANGCAATGGCAGCTAT

O2766 6O 234 42O18 NCOOOOO7. 11 96.OOf O51. ACAGCATACAAAGGNGTAATATGAAGTAA

O483 450 24 O994.51 NCOOOO14. 33 O54924 AGAAAATTGAATAANAATGGTAGCTAAGC

O484. 415 2.4383938 NCOOOOO 6. 671825. O ACTCCTCTTCCATTNACATTATTGTTGAA

OSO4647 24 O84733 NCOOOOO8. 782355.57 ATAGTCAAGTTGAANGAATATACATTTTT

O5145 O1. 245 O1683 16 NCOOOO16. 79 070531. TGTGGGAACAACTANTTGTGCATGGAATC

Off375 2.426868 O NCOOOOO1. 8 216245. Of3 TTATTCATCTATTANAGAAAGTAGCAAAA

O787862 24575921 NCOOOO1 O. 8 12O551865 CTGTGCACTGGGCANTGCGCTGATAGGCA

O7935712455.2848 NCOOOO1 O. 8 44768383 CAGGTCAAGTCTAGNTAGCTGTGGGGCAG

O818896 23499.368 NCOOOOO9. 9 98253743 TCAGTTCAGAATCCNCAGAAAAGTTAGTG

O819626 24554.249 NCOOOOO9. 9 13 O1. Os31 O CCCTGGCTGGTTACNTAGGGCTACCTGTC

O8421.92 24 OO1678 12 NCOOOO12. 236 6.1565. GGAAAAGCTTGGATNCAAAAGTAAATAAT

O842616 23428232 12 NCOOOO12. 258.436.38 CATCTTGGAAAATANGCATTTATATGTTT

O844149 243 64 474 12 NCOOOO12. 3221842s AGTCAGATGTATCTNTTTTTTCCTTTTTA US 2008/0280955 A1 Nov. 13, 2008 59

TABLE 9- continued

SNP information (Chromosome, Accession and Position in Human Genome, NCBI Build 35; rSID and SSID in NCBI dbSNP database)

rs ID sSID Chi Accession Position Assayed Sequence

O866652 23.753035 5 NCOOOOO5.8 170933 O7 O TAACTACTATGCAANAGGAACACTGACCT

O873 421 23 6545O1 14 NCOOOO14.7 91.888 484 AATATGGTATAGCCNTACAGGTGAATTTA

O933 481 24333 OO6 2 NCOOOOO2.9 15 O56 6491 TTCTCCTCAGATCANTATTATTTCAGAGG

O984.781 24 O88381 9 NCOOOOO9.9 119806337 TGCACACTTTAGAGNTTAGAAAATCCAGG

O2381.523589 O25 11 NCOOOO11.8 1596.3815 ACACATTGTTACTGNTCCCACCACAGAAT

O44839 23.99 O157 12 NCOOOO12.9 198O1 O39 GCTCCACAACCCTCNGGCAATACCTAAAT

Of 7567 24213923 17 NCOOOO17.9 66988 O39 AAACAGTAGTTGCCNGCTTCCCACGTGCA

O78544. 23792 983 17 NCOOOO17.9 4909235 CTCTGGGTTCAGCCNGTCTCCTGTCATTC

126.91923691626 2 NCOOOOO2.9 836.47732 TGAATTTGGGCTTTNCTCGATTCATGATT

1447 OS 23490584 9 NCOOOOO9.9 75819842 ATTGCTTATGAGCTNTGGAATTAAGTGGT

1515 O8 245 OS283 18 NCOOOO18.8 65285990 GTTTGTGTAAATACNCAGTTTCCTGTATC

171159 24359 O37 12 NCOOOO12.9 37.88739 O. AATGGATACACTGANGGTTAGTGGCTCCT

176454. 242145.46 12 NCOOOO12.9 655.38533 TTTTTTGACTTTTTNTTGCAGATTCTAGO

1773 15 24 61.14 O8 12 NCOOOO12.9 673 O8563 CAGGAAACCTTGTCNAATGCGTGATTTTA

2094. O3 2.3848.737 1 NCOOOOO1.8 69392 O83 CTCTCTTTTAACAANGCAGTGCTCAAGAT

2094. Os 24251883 1 NCOOOOO1.8 693.96 620 TACTTTGTCCACAGNGCACTGAGCTCTGG

582478 242 76808 1 NCOOOOO1.8 213 O58598 AAAAGCTACAAATTNATGAAGTATCTAGG

6.42164. 24189783 16 NCOOOO16.8 96.64807 TGTGTGCATTATGCNAAGCAAGGAATACT

651604 247 O5544 17 NCOOOO17.9 66948104 CGGGCCATAAAACCNAGACCGCCAGAAAC

715.174. 24287551 3 NCOOOOO3.9 72145 688 ACAAGCTTGTTAGCNGATGAGCTGGGACA

7.338 O124236O71 4 NCOOOOO4.9 84 O16807 TTTATTTTTTTGCCNATAAGAAAGATCCC

82O556. 23629.748 11 NCOOOO11.8 122579926 TTGATACGACTTGANTACCCAAGGCTGAG

8.33134 23952248 12 NCOOOO12.9 22157469 CACTTGTAACCTTCNGTGATTAGATCCAG

89 2547 23f2O603 2 NCOOOOO2.9 195208025 GAAATGCTAAATGGNGAAAGCAATCTGAG

9141 04 2364 6668 22 NCOOOO22.8 355771.18 CTGGCGGTCTGTTCNCGTCAACATTTAGA

99.459 O 23457881 8 NCOOOOO8.9 111886.247 TTGGAATCCAAAGCNTGTCTCTTTTGAGA

2O18552 23514,195 13 NCOOOO13.9 697.28319 TTCAACACTGTCCCNTATCTTTCTATACT

2O54 491239 Of 649 4 NCOOOOO4.9 111168295 ACT CAAAGCCAAGTNTTAGACTAGCAGAA

21494 83 24 O4 643 O 16 NCOOOO16.8 789 SO963 ATAACATAAAAAGTNTTCATTCACTCGCT

2162O84 242174O9 16 NCOOOO16.8 265 56.972 TACAAATGGTCACANAACTTACCCTACAC

2199 OO3 23773 6.87 6 NCOOOOO 6.9 553 04546 GAGAGCAATGCTTANGTGATGCAAATGGA

22O4525 24 622323 6 NCOOOOO 6.9 45899.891 CTGGAATCAAGGTCNCCTTCTTGGTCTTT

259 O632 241 O9096 14 NCOOOO14.7 5.1099. Of 1 ATTCCCTCACTCCANCCCAAGGGCAATTT

2724393 2425.1682 1 NCOOOOO1.8 21828492 O CCAGAGATTACAGCNTGAAGGGTTTTGAG

3O26628 24 6 5 4234 2 NCOOOOO2.9 1953.39.111 TAAAATCCTACATANCTCCCTTGGGCACT US 2008/0280955 A1 Nov. 13, 2008 60

TAB LE 9- continued

SNP information (Chromosome Accession and Position in Human Genome, NCBI Build 35; rSID and SSID in NCBI dbSNP database)

rs ID sSID Chr Accession Position Assayed Sequence

3O37781. 235.58.482 NCOOOO20 9 3 O96893 CTCTAGGAGCCCCTNGCCCTTGCAGCCCA

3 O67759 23.274 631 NCOOOOO3. 9 27 OS2735. AAGATGAGGCCCCANGGTTTTGGAATGCT

3.157045. 23923. Of O NCOOOOO5. 1O 6126.646 CTACACAAAAATTAN CACTTGGGCAGGG

3235-422 24 4294 O6 NCOOOOO7. 1682,728 O AAGAATACTATCTTN TTTCTCACCACAG

32.89879 24579 O23 NCOOOOO9. 1 OO34824 GCAACTTCATTGGAN TAGACAAGACATGA

34 O9142,231933 45 NCOOOOO2. 32577788 CAGCGGAATTAGACNCAGGACTTTGGTTT

683.958723925797 NCOOOOO2. 2O386.3556. AAGAAGAAGATTTTN AGTTCTGTTTATG

6872491234 O984.1 NCOOOOO5. 352 OO652 AGTCCAG TCAGAGN GATGCCAGGATTA

6873.956. 234 10589 NCOOOOO5. 4434824 6 AATAATGGA GTTANCACTTAAGCCTCTG

68813 6 O24 O88842 NCOOOOO8. 111994.964 GTCCAAC TTCCCAN CTACCCCAACTCA

6892924, 23313927 NCOOOOO5. 23886969 CTAACAT TTGTTGN TCTACCACCTTTA

68940822.3380.583 NCOOOOO 6. 83 094 644 GGATAACAG GGGANGGTGAGGCAAAAGC

6.8991.63 24 O72251 NCOOOOO8. 1250.58541 CAAAATA GAGCTCN GGTCTAACTACA.T

6902330 23.459589 NCOOOOO5. 34,251. O6 TGCCCATGTTCTGAN TTATCAGGCCAGC

692.9452 23997.965 12 NCOOOO12. 25863384 ATCTTGT TTGGCANCTTGATGACTACAT

6944 O2623955249 12 NCOOOO12. 113226862 GCACAGGGGACTCCNGACAGATGTGATAT

6969.422 24 OO3810 15 NCOOOO15. 76113254 ATATCAT TTTCCTNTTTACTTGTACTTT

6976 O54. 237994 63 16 NCOOOO16. 265 61984 TCATTGACACAGTTNACATGCCAGGGTCA

7 OO1863 24 Of 944 O 22 NCOOOO22. 39.0838O8 ATCTAGCAGCATGANTCATCAGCTCTGGT

7 O12108 234 O36O1 NCOOOOO4. 1284 O1930 TCCGATTTGCAGTTNTAGTTCGACTAAAT

7 O14088 23.237521 NCOOOOO4. 89637609 TTTCTATAAAAGTTNGTGATACAATGATG

7 O293 64. 2415238O NCOOOOO4. 1542 SO 677 TTAGACACCCTCTCNGTGGGGCAAAATTG

70355 O423896 631 12 NCOOOO12. 103284. O8 O ACTACTTGGACAGTNACCTGAACATCTCA

7 Off1.4.4. 233 6.8 681 NCOOOOO5. 173620078 GTGGTTGAACCTTGNAGAAATGTGTTAGA

7081,286 24 OO4586 13 NCOOOO13. 2433655 OAGGGACACATTCAGNACCCAATAACTGTA

71O142O 24 O99 431 14 NCOOOO14. 33 O52891. AGGAGAAGACTTGCNTGCCCAGGCTTGCT

71317 O1238,539 O2 NCOOOOO1. 84 613522 AATATAAAACTAAANGAGATGAACATTGG

713.7494 24 Of 4774 NCOOOO10. 1565.1878 TCAAGAAAAGATGANGTTTGCATTCTCTA

7143871.233 61 OSO NCOOOOO7. 11 2 O921,548 GAACGTAGTACTCCNTTTGACTTTGAGAA

7159146 24159741 NCOOOOO7. 11 8892 O97 TTGGTGCATTTAGTNCAAACAGCTCCCAA

717 O923 23739703 NCOOOOO5. 13643O319 GAGATTATTTGTAANCACAGTGTTTCATG

71988 44, 244 17517 NCOOOOO 6. 11. Of O48 ATGAATAGAAGCATNTTTGTGTCTACAAC

7249385 24426511 NCOOOOO 6. 1363 12771. CTTATATTTAAGACNGCTTAGATTTTTTA

725442424. 4164 O2 NCOOOOO8. 59188993 AAACTTCATAAAGCNAGGAAAGAAGATAA

7263496 24 419 OO2 NCOOOOO5. 13790444 TCACCTCCTCGGCTNTCCTTTTTGTGTTA US 2008/0280955 A1 Nov. 13, 2008 61

TABLE 9- continued SNP information (Chromosome Accession and Position in Human Genome, NCBI Build 35; rsID and SSID in NCBI dbSNP database) rs ID ssID Chir Accession Position Assayed Sequence

7283421.247304.26 X NCOOOO23.8 3262O908 CTTTATGCAGGATTNAGTTTTACAGGATA

72877 45 246 22099 5 NCOOOOO5. 8 1426352O8 TCAGTACTTTTAAGNCAATGCAACTTTAA

72.89925 24221.325 3 NCOOOOO3.9 1869.17362 CTTACCTGGTGGCTNGTTCGTGGAATTTA

7315298.24634262 1 NCOOOOO1. 8 174OO3454 TCCTGGACTGGCTTNACTGTACTCTCCCA

7315903 24524731. 16 NCOOOO16.8 19277945 TTAAAAAAAATCTTNTGTGGTTGGCTATC

7348962 2454.2111. 8 NCOOOOO 8.9 688523 48 GACGACAGATGTCANAAAACATAAAAGTA

737875124.5451.85 8 NCOOOOO8.9 78.828 OAGTTCTGAAGATTTNCTTTGAGTTTTTAA

739.9569 24242 512 1 NCOOOOO1.8 33 02116. GGGCTCACAACGGGNGGTCATGGTTGCGG

7412366 246.49394 2 NCOOOOO2.9 14 65 O9.545 CTAGATAGGGGAACNGAGCAGCTAAATGA

742 6593 24 6 5166 O 6 NCOOOOO 6.9 3.2716 OSS AGACCATGCCTGATNGGTGTTTTACACAT

7428526 24.54 O 628 11 NCOOOO11.8 70229,376 AGCCAGGGAAGCCANCCATCCAAGAGGGA

742.9548 2371.1465 4 NCOOOOO4.9 77667273 GCAAAAACCATAGCNTTATTGGGCTTGGG

7495754. 24562333 8 NCOOOOO8.9 82315105 AATACGATGGTGACNTTTCAAAAATCTGG

7529372 24.655122 4 NCOOOOO4.9 416 O7138 CTTTTTCAGGCTTGNAAATGCTCATGCTA

754.127O 24456879 18 NCOOOO18.8 1O3 61 O3s ATTTTAATCTGGTTNCACATTTGTCGTCA

7572655 24573436 12 NCOOOO12.9 673.71477 AAAAGAGAAAATTGNAAAAAGTAGGTGAG

7573852 24474156 18 NCOOOO18.8 34.9 O858 TACATTCTTTGGGTNTGAACATAGTTTTA

7622991 246 81239 5 NCOOOOO5. 8 13196O 652 TAACTCTGATAGGTNATGAGGAGCCAACC

765228724284O76 2 NCOOOOO2.9 2O2S7865 TCTGATCGTAAAACNGTGGACGCTGAGCA

76594 37 24276737 1 NCOOOOO1. 8 174O38 044 TTAAAATATATCAANGTATCTGCAGTCCG

771.911224194884 7 NCOOOOO7.11 414467OO GATTGAACAGGACTNTTTGTTAATTCTAC

7763421. 24392.771 4 NCOOOOO4.9 3 O13 6 O1s AACATCATTTTTACNGTTATTCTTAAGAT

778 4735 244 O6 OO1 8 NCOOOOO8.9 129 O2O34 ACATTTCATTGCAGNGATAAGGGATAGGG

7793991 2450942O 8 NCOOOOO8.9 62729142 CAGCAATGAGGCAANTAAAATGCACTTGA

779697O 243 08693 4. NCOOOOO4.9 181860.565 TCAAGGTCGATATANTGATTTCTGAACAA

TABLE 10 TABLE 10-continued Gene transcripts within 10 kb of SNP Gene transcripts within 10 kb of SNP from NCBI Gene from NCBI Gene

SNP information NCBI SNP information NCBI NCBI bSNP Gene ID, Gene Location wrt NCBI dbSNP Gene ID, Gene Location wrt

rSID SSID Build 35.1. Name gene rSID SSID Build 35.1. Name gene

4007 23498869 40OS LMO2 intron 478,239 24225486 S990 RFX2 intron 324O1 23446086 S74S1 ODZ2 intron 510970 24520470 4781 NFIB intron 163299 23975386 411 ARSB intron S28374 24431617 286343 C9Crf150 down 247052 245.37584 1258 CNGB1 intron 579596 24674812 SSO34 MOCOS intron 261712 2383.1465 4O1616 LOC4O161 intron 622946 24167210 44.1632 LOC44163 up US 2008/0280955 A1 Nov. 13, 2008 62

TABLE 10-continued TABLE 10-continued Gene transcripts within 10 kb of SNP Gene transcripts within 10 kb of SNP from NCBI Gene from NCBI Gene

SNP information NCBI SNP information NCBI NCBI bSNP Gene ID, Gene Location wrt NCBI dbSNP Gene ID, Gene Location wrt rSID SSID Build 35.1. Name gene rSID SSID Build 35.1. Name gene

713286 23356479 44.1336 LOC44133 intron 3827896 23654688 S1156 SERPINA1 up 747532 24476902 58504. ARHGAP2: intron 3844OSS 23188349 491.9 ROR1 intron 8.71962 24296057 1359 CPA3 up 414O768 24704O28 397 ARHGDIB intron 8.71962 24296057 1360 CPB1 down 4397143 23258.338 10636 RGS1.4 up 886126 23389735 233.16 CUTL2 intron 4397143 23258.338 1096O LMAN2 intron 888784 23247790 6586 SLIT3 intron 4461009 24224897 145773 MGC2669 (2) intron 902271 24189394 321 APBA2 intron 446SS11 2339.9579 796.12 FLJ22054 down O17672 2466 6309 81.28 SIAT8B intron 446SS11 2339.9579 387922 LOC38792 down O2S623 246SO193 44.1632 LOC441.63 up 4565762 23.655.425 84871 FLJ14442 intron O26O71 2409.2882 406 ARNTL intron 469OOO1 23891796 118 ADD1 intron O76184. 24579881 791.54 MGC4172 up 4699.197 2323.7336 79807 FLJ13273 intron O76184. 24579881 798.93 ZNF403 intron 4746.136 24119040 1591.95 USP54 intron O78SO4 23552724 10801 MSF intron 49764O1 23739713 6695 SPOCK intron 106722 23.792505 2.7133 KCNHS intron 4976685 23258293 1096O LMAN2 intron 13O866 24652879 6439 SFTPB nonsynonymous 4982207 24578093 390443 h461 up 137895 2342O2O7 4606 MYBPC2 up 498.2689 24720936 4323 MMP14 down 137895 2342O2O7 6689 SPIB 3'UTR 5957080 24723435 392529 LOC39252 up 144963 241.37593 1368 CPM up 6681627 24276577 991 O HEHL up 194586 24284512 S7198 ATP8B2 intron 67.66574 232894.63 6480 SLAT1 intron 348994 236.88892 SO852 TRIM intron 6775742 24282737 440962 LOC44096 intron 482674 234.11034 2255 FGF10 intron 6897128 24188971 22987 SV2C intron 663588 241.37580 1368 CPM intron 7121669 24O40O26 40OS LMO2 down 671413 24410446 10395 DLC1 intron 7177340 23544375 400411 LOC4OO41 intron 745836 244311SO 2098 ESD down 7429509 23673764 6480S P2RY12 intron 748952 2460386S 9623 TCL1B up 7429509 23673764 116931 TRALPUSC) intron 748952 2460386S 27004 TCL6 down 7525479 24257106 391 O47 LOC39.104 intro 798.255 23328953 636 BICD1 intron 765.7964. 24645587 55351 STK32B intron 831369 24171766 138882, OR1N2 synonymous 7666.299 2423.6069 79966 SCD4 intron 876533 23907570 8.987 GENX-341 up 7668673 24398923 57533 TBC1D14 intron 905325 24422327 1740 DLG2 intron 7670013 23742709 23O22 KIAAO992 intron 2O2S122 24417281 28S768 LOC28576 intron 7757529 244973O1 9324 HMGN3 up 2028.088 243O7687 389136 FLJ38507 down 7802597 23534456 23249 KLAAO960 intron 2O731.45 244S1923 81O3O ZBP1 nonsynonymous 7807431 23351577 64.409 WBSCR17 intron 2O781.31 235458.87 9811 KIAAO427 intron 7855874. 24305257 158O38 FLJ31810 intron 2119099 24564146 83.643 CCDC3 intron 7909.516. 2338SO28 83938 C10orf11 intron 224O142 2347S360 6923 TCEB2 down 796.4255 2379.7169 11163 NUDT4 intron 224O142 2347S360 23S24 SRRM2 synonymous 8O24294 2374.3009 390641 LOC39064 up 2270927 241891.33 22987 SV2C nonsynonymous 8O32896 245236OS 400411 LOC4OO41 up 2277594 24.126822 SO46 PCSK6 intron 8091.352 23479883 7S3 C18Orf1 intron 22 77937 24022954 SS568 GALNT10 3'UTR 81.0356O 24225485 S990 RFX2 intron 2278381 23935144 1809 DPYSL3 intron 8108576 2363.1018 390980 LOC39098 intron 2281628 24O995O2 64O67 NPAS3 intron 93OO16O 24001822 666O SOXS intron 2285646 23S49839 55972 MCFP intron 9306955 24651330 10744 PTTG2 down 2375592 246843O1 25796 PGLS down 9314751 23431158 7967O ZCCHC6 down 2375592 246843O1 199786 BCNP1 up 9314751 23431158 81689 HBLD2 up 2388062 23321060 1444.02 CPNE8 up 936,7359 23768890 389.396 LOC38.939 nonsynonymous 2412711 2396.0627 825 CAPN3 intron 9395SO4 24687SO9 389.396 LOC38.939 down 2412711 2396.0627 64397 SH3BP3 down 982666.2 24296064 1359 CPA3 up 2426778 23452.529 79716 NPEPL1 down 982666.2 24296064 1360 CPB1 down 2426778 23452.529 3912S8 LOC3912S down 9996218 23160392 24617S CNOT6L up 243709S 23374778 3908 LAMA2 intron OOS763O 23410686 2255 FGF10 intron 2SSO62O 241958OS 51741 WWOX intron O173398 23696.624 11479.3 FMNL2 intron 2S50621 241958.06 51741 WWOX intron O4834SO 24O994S1 64O67 NPAS3 intron 2579875 23534378 1371.96 MGC2743(2) intron O77937S 2426868O 44O71S LOC44O71 intron 2664538 23574543 4318 MMP9 nonsynonymous O793571 245S2848 83937 RASSF4 up 2682968 24.278304 2272 FHIT intron O818896 23499368 9568 GPRS1 intron 2738591 241958.21 51741 WWOX intron O819626 24554249 392,395 LOC39239 intron 2764951 231991.94 7399 USH2A intron O842.192 24OO1678 666O SOXS intron 28S 1391 245S1945 875 CBS intron O844149 24364474 636 BICD1 intron 291 O104 24107752 57122 NUP107 intron O873421 23654SO1 123041. SLC24A4 intron 2991.345 23837190 59269 HIVEP3 down 102381S 23589025 55553 SOX6 intron 3732768 23673768 116931 TRALPUSI synonymous 114470S 23490584 5125 PCSKS intron 3746229 23631096 390980 LOC39098 down 1151508 24505283 22O164 DOKSL intron 3775561 24662115 3660 IRF2 intron 117731S 2461-1408 5908 RAP1B intron 3781575 234988OO 40OS LMO2 intron 1582478 24276808 2104 ESRRG down 3795294 23668004 6920 TCEA3 intron 17338O1 24236O71 79966 SCD4 intron 38221.96 24372212 2798 GNRHR intron 182OSS6 23629748 798.27 ASAM up 3827896 23654688 866 SERPINA6 down 1914-104 23646668 4689 NCF4 up

US 2008/0280955 A1 Nov. 13, 2008 69

- Continued

<210 SEQ ID NO 2 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 2 cagacct tct tccanctgta aaatticcca 29

<210 SEQ ID NO 3 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 3 aagaggtaac C ccting acct aagaggaaa 29

<210 SEQ ID NO 4 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 4 atttcttgag aagtncaa.ca acacagtga 29

<210 SEQ ID NO 5 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 5 caaaatttgc titagntaact tcc ccgggg 29

<210 SEQ ID NO 6 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 6 agatttgaga aaagnttcaa aatgcaaat 29

<210 SEQ ID NO 7 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: US 2008/0280955 A1 Nov. 13, 2008 70

- Continued <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 7 tagtgttgtgc tactnc ct at ttggataac 29

<210 SEQ ID NO 8 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 8 gctagtag at tt cangtcta tta acagtic 29

<210 SEQ ID NO 9 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G <4 OO SEQUENCE: 9 cittgct ct ct aat cnt cago atctt cqtg 29

<210 SEQ ID NO 10 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 10 tagaatgcac aaatnagcat aaaagaaaa 29

<210 SEQ ID NO 11 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 11 aaatatgaat aattntttga ccagtactt 29

<210 SEQ ID NO 12 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 12 US 2008/0280955 A1 Nov. 13, 2008 71

- Continued accataaaaa gacanttct c agcagagac 29

<210 SEQ ID NO 13 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 13 ggcaatgagg Cttang tatt ttgtttct 29

<210 SEQ ID NO 14 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 14 atgct caa.ca gcc antaaga t ctitt caga 29

<210 SEQ ID NO 15 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 15 aaatgcacat gigatingttitt gaccacagc 29

<210 SEQ ID NO 16 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 16 cc.gtttgaca aggtntctgg Ctgatataa 29

<210 SEQ ID NO 17 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 17 taagaag.cat tdatncagga aatat citta 29

<210 SEQ ID NO 18 <211 LENGTH: 29 &212> TYPE: DNA US 2008/0280955 A1 Nov. 13, 2008 72

- Continued <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 18 c caggcaatt cat cntgtct caaggcaga 29

<210 SEQ ID NO 19 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 19 aatgagagct totanataaa agt cottgc 29

<210 SEQ ID NO 2 O <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 2O ttctgcaa.cc togctncaacc agg act citt 29

<210 SEQ ID NO 21 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 21 ctggct cocc gct cinatggt titt cagotg 29

<210 SEQ ID NO 22 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 22 tgagggtgaa attting agag ctgaggaaa 29

<210 SEQ ID NO 23 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G US 2008/0280955 A1 Nov. 13, 2008 73

- Continued <4 OO SEQUENCE: 23 ttaaggcagt gcc.cna actt titatic tatt 29

<210 SEQ ID NO 24 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 24 agcc caatag tictgnagttt gtc.ca.gaag 29

<210 SEQ ID NO 25 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 25 gccaagtttc taccing aggc titggct tcc 29

<210 SEQ ID NO 26 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 26 tagactittgg agcc.nattitt Cttctitt.ca 29

<210 SEQ ID NO 27 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 27 catcct citat tittgnacgct cagt caccc 29

<210 SEQ ID NO 28 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 28 aacacctgta cacanaactg caggg.ccct 29

<210 SEQ ID NO 29 US 2008/0280955 A1 Nov. 13, 2008 74

- Continued

<211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 29 gtaagaatgt citt.cnttaca gaataatgc 29

<210 SEQ ID NO 3 O <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 30 tctgct atta ccagnactict t cagtatta 29

<210 SEQ ID NO 31 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAME/KEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 31 ttcactittag aaatnaatgg attattagt 29

<210 SEQ ID NO 32 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 32 tctggc catc cct gnctgga acctgttct 29

<210 SEQ ID NO 33 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 33 ttagcatacg ttittntaata attatgtta 29

<210 SEQ ID NO 34 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 US 2008/0280955 A1 Nov. 13, 2008 75

- Continued <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 34 taaatgtggg acctnagatt toga acccta 29

<210 SEQ ID NO 35 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 35 agaatgagtt ctittntgcag titc cattgg 29

<210 SEQ ID NO 36 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 36 agatgattta ggctnaga aa gaggaggcc 29

<210 SEQ ID NO 37 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 37 gatcgatat c td tantttga ctittctitat 29

<210 SEQ ID NO 38 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 38 ctgtct tagg cactnagcca caatctorala 29

<210 SEQ ID NO 39 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 39 ttgcagcc ct cacantctgg ttctggaag 29 US 2008/0280955 A1 Nov. 13, 2008 76

- Continued

<210 SEQ ID NO 4 O <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 40 gtgaggcctg ggacntttitt aagat.cgct 29

<210 SEQ ID NO 41 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 41 accc.ccagca aaacnggatt tdtttgttt 29

<210 SEQ ID NO 42 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 42 ctaaaatcta ctittnatatt tot cagoct 29

<210 SEQ ID NO 43 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 43 attittgactg gcgc.ngcaga atgaggagg 29

<210 SEQ ID NO 44 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 44 tctic ctggaa agacinggctic tict Caggitt 29

<210 SEQ ID NO 45 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: US 2008/0280955 A1 Nov. 13, 2008 77

- Continued <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 45 cgtgactitat aatting taga cacticagtg 29

<210 SEQ ID NO 46 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 46 tittattitt ca cccanaaatt tacatagaa 29

<210 SEQ ID NO 47 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G <4 Oos SEQUENCE: 47 tgttittcaat gtttntgctg atttittitt c 29

<210 SEQ ID NO 48 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 48 cittctggaat at cantgaat cittgaatgt 29

<210 SEQ ID NO 49 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 49 tacctitat co ccating agac gtc.gctgga 29

<210 SEQ ID NO 50 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 5 O US 2008/0280955 A1 Nov. 13, 2008 78

- Continued ctataaggcc gtacnttgtc. tcc titt cat 29

<210 SEQ ID NO 51 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 51 tagittatgac tt canaccaa aat attact 29

<210 SEQ ID NO 52 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 52 tatgtcatac cattnatcgt gatgct cala 29

<210 SEQ ID NO 53 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 53 aatatgagac at Canaatac agagaatga 29

<210 SEQ ID NO 54 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 54 tgctictaatt toccinatgtc. gigt tactat 29

<210 SEQ ID NO 55 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 55

Cttaca aggc cagcnatata ggcagc.cat 29

<210 SEQ ID NO 56 <211 LENGTH: 29 &212> TYPE: DNA US 2008/0280955 A1 Nov. 13, 2008 79

- Continued <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 56 gtacagtact gtttingaagg ttt tatgct 29

<210 SEQ ID NO 57 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 57 aattcaatca gagtnc cagt cactaataa 29

<210 SEQ ID NO 58 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 58 atttctaagc tictang tagg togaaatcc c 29

<210 SEQ ID NO 59 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 59 caggitt tatt attanaaaag toagttgtt 29

<210 SEQ ID NO 60 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 60 titatgaccat gtgantaa.ca aaaattctg 29

<210 SEQ ID NO 61 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G US 2008/0280955 A1 Nov. 13, 2008 80

- Continued <4 OO SEQUENCE: 61 taaaactata acacncagtt to cagagca 29

<210 SEQ ID NO 62 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 62 ttagggittag ttgtnacaga ttgct cagt 29

<210 SEQ ID NO 63 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 63 tcaaattgaa gtttnaattg gtaaatggg 29

<210 SEQ ID NO 64 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 64 gcgg catggg gaggincagaa tagataagg 29

<210 SEQ ID NO 65 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 65 gattgcctica gcc tint gatg atgtttaga 29

<210 SEQ ID NO 66 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 66 aatatttgca ggatingtott agaatt cat 29

<210 SEQ ID NO 67 US 2008/0280955 A1 Nov. 13, 2008 81

- Continued

<211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 67

Cagggagttc tt Canaagtg gttatcct a 29

<210 SEQ ID NO 68 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 68 gggaggcaag ttgntagtic Caagtaaaa 29

<210 SEQ ID NO 69 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAME/KEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 69 cagact tcct c cittntagga ct citctgag 29

<210 SEQ ID NO 70 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 7 O agtgtgat ct gaatntttgg gtatic ctitc 29

<210 SEQ ID NO 71 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 71 tagcagataa tittnaaatt aaggaatga 29

<210 SEQ ID NO 72 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 US 2008/0280955 A1 Nov. 13, 2008 82

- Continued <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 72 aaaggc catt tttnttggg totaacaat 29

<210 SEQ ID NO 73 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 73 ggaggcatca tacancCtga Cittagaaat 29

<210 SEQ ID NO 74 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 74 tgaagt caga gtCangaggg C cagotgca 29

<210 SEQ ID NO 75 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 75 aattittcaac toatntgaaa acatgatga 29

<210 SEQ ID NO 76 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 76 caattact at tdgcng tat c titt ct ctitt 29

<210 SEO ID NO 77 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 77 agacaataca taangaatg caactgtgt 29 US 2008/0280955 A1 Nov. 13, 2008 83

- Continued

<210 SEQ ID NO 78 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 78 ctgtcc tocc caccinc actg. taagttctt 29

<210 SEQ ID NO 79 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 79 aaaaaataac cacant gcca ccaaaatat 29

<210 SEQ ID NO 8O <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 80 tggct tcc.gg gctantgaat ttaatttga 29

<210 SEQ ID NO 81 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 81 tacic cct tag cittanaagica aaaaagaaa 29

<210 SEQ ID NO 82 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 82 ttgaggaatg tacanattitt attctgttg 29

<210 SEQ ID NO 83 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: US 2008/0280955 A1 Nov. 13, 2008 84

- Continued <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 83 ttgctggggg. Ctctinggctg. Cagaaagaa 29

<210 SEQ ID NO 84 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 84 atatgcc.caa totantctga cct tcaccc 29

<210 SEQ ID NO 85 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G <4 Oos SEQUENCE: 85 catc to tcca aagangctica ggit ct cogit 29

<210 SEQ ID NO 86 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 86 ctittgata at ttggingtott agtttgttt 29

<210 SEQ ID NO 87 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 87 aaaatcagtg ggcc.ngatac tagagatag 29

<210 SEQ ID NO 88 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 88 US 2008/0280955 A1 Nov. 13, 2008 85

- Continued t ccc.gcagta gaagnt tagt tagacgtgg 29

<210 SEQ ID NO 89 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 89 atatgcaaat tt cant atta actttacaa 29

<210 SEQ ID NO 90 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 9 O ggcaa.gcagg C cc Cnggc at ttcaaag.cg 29

<210 SEQ ID NO 91 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 91 t cct ctdagc act cnggcat ttgtcattg 29

<210 SEQ ID NO 92 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 92 gttcagggct ctittntatac ctdaggcct 29

<210 SEQ ID NO 93 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 93 titt caggaat aaaancaa.ca caattattt 29

<210 SEQ ID NO 94 <211 LENGTH: 29 &212> TYPE: DNA US 2008/0280955 A1 Nov. 13, 2008 86

- Continued <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 94 c cct gaccaa aaaanaaaag atttitt cat 29

<210 SEQ ID NO 95 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 95 tgttatatac tagantttga tagct atta 29

<210 SEQ ID NO 96 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 96 gccttgaaag caccing agag tictagt ct c 29

<210 SEQ ID NO 97 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 97 ttatatat ct titc.cnttt at ttaggtott 29

<210 SEQ ID NO 98 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 98 citcaattgac atttingct co agtgtcgag 29

<210 SEQ ID NO 99 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G US 2008/0280955 A1 Nov. 13, 2008 87

- Continued <4 OO SEQUENCE: 99 titat ctaaat tctgnt ctitc act caatat 29

<210 SEQ ID NO 100 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 1.OO gttc.cgggaa gtc.cnt citco agcaggaac 29

<210 SEQ ID NO 101 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 101 gcago accct gtatntgata ttaat attt 29

<210 SEQ ID NO 102 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 102 ttctitt cago cct gnt ct ct aaaggatgg 29

<210 SEQ ID NO 103 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 103 cactitcagat tccant cqaa tacattaga 29

<210 SEQ ID NO 104 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 104 gCagatgc cc ggctingtggit talacc Caag 29

<210 SEQ ID NO 105 US 2008/0280955 A1 Nov. 13, 2008 88

- Continued

<211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 105 gcc.gcatc to tdatint caga gcatttaca 29

<210 SEQ ID NO 106 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 106 aggact ctac accCnggacg gcaatgctg 29

<210 SEQ ID NO 107 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAME/KEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 107 agct cotaca tdt cnttittg agacctitat 29

<210 SEQ ID NO 108 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 108 acgtgattac aaatingggaa aagaggggc 29

<210 SEQ ID NO 109 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 109 tatacacaca gaaanaaata citggtgaga 29

<210 SEQ ID NO 110 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 US 2008/0280955 A1 Nov. 13, 2008 89

- Continued <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 110 aaattt cata tdaanggtgg gcttittctt 29

<210 SEQ ID NO 111 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 111 aactgaagat tcc cnttt at ttittct coa 29

<210 SEQ ID NO 112 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 112 cattat caca aaacntaata cct daagat 29

<210 SEQ ID NO 113 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 113 alacctgaccc ticggingtgtc. ttctgtaa 29

<210 SEQ ID NO 114 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 114 ttcagttagt ctaant tatg aggatatat 29

<210 SEQ ID NO 115 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 115 atggct ctitc gtc.cnatgat t ctaaag.cc 29 US 2008/0280955 A1 Nov. 13, 2008 90

- Continued

<210 SEQ ID NO 116 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 116 aaaagaattt ttagnt ccta tdt catagt 29

<210 SEQ ID NO 117 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 117 catgcaatca catcncagca gcagttgat 29

<210 SEQ ID NO 118 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 118 ggcaaagt at ttgtnattag gaat atctg 29

<210 SEQ ID NO 119 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 119 gCaggcttag ticacnttgat ggatctgtc. 29

<210 SEQ ID NO 120 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 120 ggcttittaaa gttcncacag acaggcatc 29

<210 SEQ ID NO 121 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: US 2008/0280955 A1 Nov. 13, 2008 91

- Continued <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 121 cctgtc.ttac ttggingttgt cdagttcct 29

<210 SEQ ID NO 122 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 122 actatataga caaangcatg agagcacala 29

<210 SEQ ID NO 123 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G <4 OO SEQUENCE: 123 cattatttat cat cnt caac attattgct 29

<210 SEQ ID NO 124 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 124 taaaggaagg cagc.ngagta tattgggaa 29

<210 SEQ ID NO 125 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 125 gcatgagtac aag Cngaggit to a catacc 29

<210 SEQ ID NO 126 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 126 US 2008/0280955 A1 Nov. 13, 2008 92

- Continued acacaattct taatntttgg at caggcat 29

<210 SEQ ID NO 127 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 127 c cattat cac cittanttaca gcaat citct 29

<210 SEQ ID NO 128 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 128 tgcc caacgt gtgangtcat gccaccalag 29

<210 SEQ ID NO 129 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 129 atat ctitt cotttgnatcaa acagaacag 29

<210 SEQ ID NO 130 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 130 ttgctcaaat aaacngttaa tttgtctaa 29

<210 SEQ ID NO 131 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 131 t cagctgctgaag.cnactga attacaatg 29

<210 SEQ ID NO 132 <211 LENGTH: 29 &212> TYPE: DNA US 2008/0280955 A1 Nov. 13, 2008 93

- Continued <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 132 agattgttgtc. tt cantgtta aattagata 29

<210 SEQ ID NO 133 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 133 gactggagat gcacnagggg ccagattgt 29

<210 SEQ ID NO 134 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 134 tgttggggtg tctancaata gggcctgat 29

<210 SEQ ID NO 135 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 135 caacatgctg attant caag tta acacct 29

<210 SEQ ID NO 136 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 136 acattccagt agaanaagta aaaagccala 29

<210 SEQ ID NO 137 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G US 2008/0280955 A1 Nov. 13, 2008 94

- Continued <4 OO SEQUENCE: 137 agataaag.ca gacancaiaca aag cagaga 29

<210 SEQ ID NO 138 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 138 agccataaaa agaging tacg cca accc.cc 29

<210 SEQ ID NO 139 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 139 cittaatcttg attantgggc ticagaatgt 29

<210 SEQ ID NO 140 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 140 ctattaccaa gttcngtcat tagagcagt 29

<210 SEQ ID NO 141 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 141 aaaa.ca.gcat gggcnic aggc cagttcaaa 29

<210 SEQ ID NO 142 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 142 aatcagattt caaanctcca gttccattt 29

<210 SEQ ID NO 143 US 2008/0280955 A1 Nov. 13, 2008 95

- Continued

<211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 143 acticagottc ctatntgttt ttgtaagcc 29

<210 SEQ ID NO 144 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 144 aagcacgggt atctint acac aaataagtt 29

<210 SEQ ID NO 145 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAME/KEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 145 atgaact cat citatintttitt atact citac 29

<210 SEQ ID NO 146 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 146 cagagcacag ggagnacctg cggcttitta 29

<210 SEQ ID NO 147 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 147 t cccaataga aatgnttgaa aatatgaaa 29

<210 SEQ ID NO 148 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 US 2008/0280955 A1 Nov. 13, 2008 96

- Continued <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 148 gtgacaac cc tittangctgt gigtaacaaa 29

<210 SEQ ID NO 149 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 149 tgtaactggc tigaantgaaa ttgactaca 29

<210 SEQ ID NO 150 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 150

Ctcatgttgg atctncctica aggcattcc 29

<210 SEQ ID NO 151 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 151 aagggccaag tatncaggt titt coagaa 29

<210 SEQ ID NO 152 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 152 tctgctctgc citt Cng tact tcc.cgcggc 29

<210 SEQ ID NO 153 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 153 ttct cqtt at tdggincacaa gaaaaag.ca 29 US 2008/0280955 A1 Nov. 13, 2008 97

- Continued

<210 SEQ ID NO 154 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 154 taccagtggit agttntgatt acatalagta 29

<210 SEQ ID NO 155 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 155 atgtagccaa tittgntgtta aaaaaatag 29

<210 SEQ ID NO 156 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 156 gggactgttt titc.cncaaag gtttatctt 29

<210 SEQ ID NO 157 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 157 gtcc tittctg act gnc aggt gttatacaa 29

<210 SEQ ID NO 158 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: <221 NAMEAKEY: misc feature <222> LOCATION: 15 <223> OTHER INFORMATION: n = A, T, C or G

<4 OO SEQUENCE: 158 tittaatgttt atc.cntatgc attitat cac 29

<210 SEQ ID NO 159 <211 LENGTH: 29 &212> TYPE: DNA <213> ORGANISM: Homo sapiens &220s FEATURE: