Genetic polymorphisms associated with cardiovascular disorders and drug response, methods of detection and uses thereof

Abstract

The present invention is based on the discovery of genetic polymorphisms that are associated with cardiovascular disorders, particularly acute coronary events such as myocardial infarction and stroke, and genetic polymorphisms that are associated with responsiveness of an individual having a cardiovascular disorder to treatment of the disorder with statin. In particular, the present invention relates to nucleic acid molecules containing the polymorphisms, variant proteins encoded by such nucleic acid molecules, reagents for detecting the polymorphic nucleic acid molecules and proteins, and methods of using the nucleic acid and proteins as well as methods of using reagents for their detection.

1 . A method of identifying an individual having an altered risk for developing an acute coronary event or a method of evaluating an individual's likelihood of responding to statin treatment, comprising detecting the presence or absence of one or more alleles of a SNP in said individual's nucleic acids, wherein the SNP is selected from any one of the nucleotide sequences of SEQ ID NOS:121-200 and SEQ ID NOS:251-410, and the presence or absence of the alleles are correlated with an individual's risk for developing an acute coronary event or likelihood of responding to statin treatment. 
     
     
         2 . The method of  claim 1 , wherein the SNP is selected from the group of nucleotide sequences consisting of SEQ ID NOs of 356, 282, 358, 270, 256, 252, 354, 357, 306, 363, 361, 295, 285, 290, 251, 293, 294, 305, 266, 409, 410, 284, 406, 276, 263, 271, 264, 353, 261, 399, and 265. 
     
     
         3 . The method of  claim 1 , comprising contacting the nucleic acids of the individual with a detection reagent, and determining which nucleotide is present or absent at a specified SNP position. 
     
     
         4 . The method of  claim 3 , in which the nucleic acids are prepared from blood cells of the individual. 
     
     
         5 . The method of  claim 3 , in which the detection reagent is a polynucleotide probe. 
     
     
         6 . The method of  claim 5 , in which the 3′ end of the probe hybridizes to the SNP in the nucleic acid. 
     
     
         7 . The method of  claim 5 , in which the probe is labeled with a reporter dye. 
     
     
         8 . A method of detecting a single nucleotide polymorphism (SNP) in a nucleic acid molecule, comprising contacting a test sample with a reagent which specifically hybridizes to a SNP in any one of the nucleotide sequences of SEQ ID NOS:1-60 and 121-410 under stringent hybridization conditions, and detecting the formation of a hybridized duplex. 
     
     
         9 . The method of  claim 8  in which detection is carried out by a process selected from the group consisting of: allele-specific probe hybridization, allele-specific primer extension, allele-specific amplification, sequencing, 5′ nuclease digestion, molecular beacon assay, oligonucleotide ligation assay, size analysis, and single-stranded conformation polymorphism. 
     
     
         10 . A method of identifying an individual having an altered risk for developing an acute coronary event or a method of evaluating an individual's likelihood of responding to statin treatment, comprising detecting the presence or absence of a polymorphism in said individual's nucleic acids, wherein said polymorphism is in linkage disequilibrium with a SNP in any one of the nucleotide sequences of SEQ ID NOS:121-200 and SEQ ID NOS:251-410, and the presence or absence of the polymorphism is correlated with an individual's risk for developing an acute coronary event or likelihood of responding to statin treatment. 
     
     
         11 . The method of  claim 10 , wherein the SNP is selected from the group of nucleotide sequences consisting of SEQ ID NOs of 356, 282, 358, 270, 256, 252, 354, 357, 306, 363, 361, 295, 285, 290, 251, 293, 294, 305, 266, 409, 410, 284, 406, 276, 263, 271, 264, 353, 261, 399, and 265. 
     
     
         12 - 27 . (canceled)