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 to treatment of cardiovascular disorders 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 for identifying an individual who has an altered risk for developing a cardiovascular disorder or an altered likelihood of responding to statin treatment, the method comprising detecting a single nucleotide polymorphism (SNP) in any one of the nucleotide sequences of SEQ ID NOS:1-517 and 1035-85,090 in said individual's nucleic acids, wherein the presence of the SNP is correlated with an altered risk for developing a cardiovascular disorder or responding to statin treatment in said individual.  
     
     
         2 . The method of  claim 1  in which the altered risk is an increased risk of developing a cardiovascular disorder or an increased likelihood of responding to statin treatment.  
     
     
         3 . The method of  claim 1 , wherein the cardiovascular disorder is an acute coronary event selected from the group consisting of myocardial infarction and stroke.  
     
     
         4 . The method of  claim 3  in which said individual has previously had an acute coronary event.  
     
     
         5 . The method of  claim 1  in which the altered risk is a decreased risk of developing a cardiovascular disorder or a decreased likelihood of responding to statin treatment.  
     
     
         6 . The method of  claim 1 , wherein the statin treatment comprises treatment with pravastatin.  
     
     
         7 . The method of  claim 1 , wherein the SNP is selected from the group consisting of the SNPs set forth in Tables 6-15.  
     
     
         8 . The method of  claim 1  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.  
     
     
         9 . An isolated nucleic acid molecule comprising at least 8 contiguous nucleotides wherein one of the nucleotides is a single nucleotide polymorphism (SNP) selected from any one of the nucleotide sequences in SEQ ID NOS:1-517 and 1035-85,090, or a complement thereof.  
     
     
         10 . The isolated nucleic acid molecule of  claim 9 , wherein the SNP is selected from the group consisting of the SNPs set forth in Tables 3 and 4.  
     
     
         11 . An isolated nucleic acid molecule that encodes any one of the amino acid sequences in SEQ ID NOS:518-1034.  
     
     
         12 . An isolated polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NOS:518-1034.  
     
     
         13 . An antibody that specifically binds to a polypeptide of  claim 12 , or an antigen-binding fragment thereof.  
     
     
         14 . The antibody of  claim 13  in which the antibody is a monoclonal antibody.  
     
     
         15 . An amplified polynucleotide containing a single nucleotide polymorphism (SNP) selected from any one of the nucleotide sequences of SEQ ID NOS:1-517 and 1035-85,090, or a complement thereof, wherein the amplified polynucleotide is between about 16 and about 1,000 nucleotides in length.  
     
     
         16 . The amplified polynucleotide of  claim 15  in which the nucleotide sequence comprises any one of the nucleotide sequences of SEQ ID NOS:1-517 and 1035-85,090.  
     
     
         17 . An isolated polynucleotide which specifically hybridizes to a nucleic acid molecule containing a single nucleotide polymorphism (SNP) in any one of the nucleotide sequences in SEQ ID NOS:1-517 and 1035-85,090.  
     
     
         18 . The polynucleotide of  claim 17  which is 8-70 nucleotides in length.  
     
     
         19 . The polynucleotide of  claim 17  which is an allele-specific probe.  
     
     
         20 . The polynucleotide of  claim 17  which is an allele-specific primer.  
     
     
         21 . The polynucleotide of  claim 17 , wherein the polynucleotide comprises a nucleotide sequence selected from the group consisting of the primer sequences set forth in Table 5 (SEQ ID NOS:85,091-85,702).  
     
     
         22 . A kit for detecting a single nucleotide polymorphism (SNP) in a nucleic acid, comprising the polynucleotide of  claim 17 , a buffer, and an enzyme.  
     
     
         23 . 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:1-517 and 1035-85,090 under stringent hybridization conditions, and detecting the formation of a hybridized duplex.  
     
     
         24 . The method of  claim 23  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.  
     
     
         25 . A method of detecting a variant polypeptide, comprising contacting a reagent with a variant polypeptide encoded by a single nucleotide polymorphism (SNIP) in any one of the nucleotide sequences of SEQ ID NOS:1-517 and 1035-85,090 in a test sample, and detecting the binding of the reagent to the polypeptide.  
     
     
         26 . A method for identifying an agent useful in therapeutically or prophylactically treating cardiovasacular disorders, comprising contacting the polypeptide of  claim 12  with a candidate agent under conditions suitable to allow formation of a binding complex between the polypeptide and the candidate agent, and detecting the formation of the binding complex, wherein the presence of the complex identifies said agent.  
     
     
         27 . A method of treating a cardiovascular disorder in an individual, the method comprising administering to said individual an effective amount of statin based on said individual's likelihood of responding to statin treatment as predicted by the alleles present at one or more SNP sites selected from the group consisting of the SNP sites disclosed in Tables 1-15.