Genetic polymorphisms associated with cardiovascular diseases, methods of detection and uses thereof

Abstract

The present invention provides compositions and methods based on genetic polymorphisms that are associated with cardiovascular diseases, particularly coronary heart disease (especially myocardial infarction) or hypertension. For example, the present invention relates to nucleic acid molecules containing the polymorphisms, variant proteins encoded by these nucleic acid molecules, reagents for detecting the polymorphic nucleic acid molecules and variant proteins, and methods of using the nucleic acid molecules and proteins as well as methods of using reagents for their detection.

1 . A method of determining whether a human has an altered risk for cardiovascular disease (CVD), comprising testing nucleic acid from said human for the presence or absence of a polymorphism selected from the group consisting of the polymorphisms as represented by position 101 of any one of the nucleotide sequences of SEQ ID NOS:1401-4006 and 5414 or its complement, wherein said polymorphism indicates said human has an altered risk for CVD. 
     
     
         2 . The method of  claim 1 , wherein said CVD is coronary heart disease (CHD). 
     
     
         3 . The method of  claim 2 , wherein said CHD is myocardial infarction. 
     
     
         4 . The method of  claim 1 , wherein said polymorphism is in the GOSR2 gene and wherein said CVD is hypertension. 
     
     
         5 . The method of  claim 1 , wherein said altered risk is an increased risk. 
     
     
         6 . The method of  claim 1 , wherein said altered risk is a decreased risk. 
     
     
         7 . The method of  claim 1 , wherein said nucleic acid is a nucleic acid extract from a biological sample from said human. 
     
     
         8 . The method of  claim 7 , wherein said biological sample is blood, saliva, or buccal cells. 
     
     
         9 . The method of  claim 7 , further comprising preparing said nucleic acid extract from said biological sample prior to said testing step. 
     
     
         10 . The method of  claim 9 , further comprising obtaining said biological sample from said human prior to said preparing step. 
     
     
         11 . The method of  claim 1 , wherein said testing step comprises nucleic acid amplification. 
     
     
         12 . The method of  claim 11 , wherein said nucleic acid amplification is carried out by polymerase chain reaction. 
     
     
         13 . The method of  claim 1 , further comprising correlating the presence or absence of said polymorphism with an altered risk for CVD. 
     
     
         14 . The method of  claim 13 , wherein said correlating step is performed by computer software. 
     
     
         15 . The method of  claim 1 , wherein said testing is performed using sequencing, 5′ nuclease digestion, molecular beacon assay, oligonucleotide ligation assay, size analysis, single-stranded conformation polymorphism analysis, or denaturing gradient gel electrophoresis (DGGE). 
     
     
         16 . The method of  claim 1 , wherein said testing is performed using an allele-specific method. 
     
     
         17 . The method of  claim 16 , wherein said allele-specific method is allele-specific probe hybridization, allele-specific primer extension, or allele-specific amplification. 
     
     
         18 . The method of  claim 17 , wherein said method is performed using an allele-specific primer provided in Table 5. 
     
     
         19 . The method of  claim 1  which is an automated method. 
     
     
         20 . The method of  claim 1 , further comprising correlating the presence of said polymorphism with said human's responsiveness to a therapeutic agent. 
     
     
         21 . The method of  claim 20 , wherein said therapeutic agent comprises an HMG-CoA reductase inhibitor. 
     
     
         22 . The method of  claim 21 , wherein said polymorphism is selected from the group consisting of the polymorphisms provided in Table 22. 
     
     
         23 . The method of  claim 20 , wherein said therapeutic agent is evaluated in a clinical trial. 
     
     
         24 . The method of  claim 1 , further comprising the step of selecting said human for inclusion in a clinical trial of a therapeutic agent or assigning said human to a group within a clinical trial. 
     
     
         25 . The method of  claim 24 , wherein said therapeutic agent comprises an HMG-CoA reductase inhibitor. 
     
     
         26 . A method of determining whether a human will respond to an HMG-CoA reductase inhibitor for reducing risk for cardiovascular disease (CVD), comprising testing nucleic acid from said human for the presence or absence of a polymorphism selected from the group consisting of the polymorphisms provided in Table 21. 
     
     
         27 . The method of  claim 26 , further comprising administering said HMG-CoA reductase inhibitor to said human. 
     
     
         28 . The method of  claim 26 , further comprising the step of selecting said human for inclusion in a clinical trial of a therapeutic agent or assigning said human to a group within a clinical trial. 
     
     
         29 . A method for reducing risk of cardiovascular disease (CVD) in a human, comprising administering to said human an effective amount of a therapeutic agent, said human having been identified as having an increased risk for CVD due to the presence or absence of a polymorphism selected from the group consisting of the polymorphisms as represented by position 101 of any one of the nucleotide sequences of SEQ ID NOS:1401-4006 and 5414 or its complement. 
     
     
         30 . The method of  claim 29 , wherein said method comprises testing nucleic acid from said human for the presence or absence of said polymorphism. 
     
     
         31 . The method of  claim 29 , wherein said CVD is coronary heart disease (CHD). 
     
     
         32 . The method of  claim 31 , wherein said CHD is myocardial infarction. 
     
     
         33 . The method of  claim 29 , wherein said therapeutic agent comprises an HMG-CoA reductase inhibitor. 
     
     
         34 . A method for reducing risk of cardiovascular disease (CVD) in a human, comprising administering to said human an effective amount of an HMG-CoA reductase inhibitor, said human having been predicted to respond to said HMG-CoA reductase inhibitor for reducing said risk of CVD due to the presence or absence of a polymorphism selected from the group consisting of the polymorphisms provided in Table 21. 
     
     
         35 . The method of  claim 34 , wherein said method comprises testing nucleic acid from said human for the presence or absence of said polymorphism. 
     
     
         36 . The method of  claim 34 , wherein said CVD is coronary heart disease (CHD). 
     
     
         37 . The method of  claim 36 , wherein said CHD is myocardial infarction. 
     
     
         38 . A method of identifying a human having an increased risk for cardiovascular disease (CVD), comprising testing a nucleic acid sample from said human for the presence or absence of a first polymorphism which is in linkage disequilibrium with a second polymorphism, wherein said second polymorphism is a polymorphism selected from the group consisting of the polymorphisms as represented by position 101 of any one of the nucleotide sequences of SEQ ID NOS:1401-4006 and 5414 or its complement, and wherein said first polymorphism identifies said human as having an increased risk for CVD. 
     
     
         39 . The method of  claim 38 , wherein said linkage disequilibrium is r 2 =1. 
     
     
         40 . The method of  claim 38 , wherein said first polymorphism is selected from the group consisting of the polymorphisms provided in Table 6. 
     
     
         41 . A kit for determining whether a human has an altered risk for cardiovascular disease (CVD), wherein said kit comprises at least one container and at least one oligonucleotide stored in said container, wherein said oligonucleotide is capable of detecting the presence or absence of a polymorphism selected from the group consisting of the polymorphisms as represented by position 101 of any one of the nucleotide sequences of SEQ ID NOS:1401-4006 and 5414 or its complement. 
     
     
         42 . The kit of  claim 41 , wherein said oligonucleotide selectively hybridizes to said nucleic acid in the presence of said polymorphism and does not hybridize to said nucleic acid in the absence of said polymorphism. 
     
     
         43 . The method of  claim 41 , wherein said oligonucleotide comprises at least one allele-specific primer provided in Table 5. 
     
     
         44 . A method of determining whether a human will benefit from hormone replacement therapy, comprising testing nucleic acid from said human for the presence of absence of LPA polymorphism rs3798220, wherein C or its complement at said polymorphism indicates said human will benefit from hormone replacement therapy. 
     
     
         45 . The method of  claim 44 , further comprising administering hormone replacement therapy to said human.