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 of determining whether a human has an increased risk for coronary heart disease (CHD), comprising testing nucleic acid from said human for the presence or absence of a polymorphism as represented by position 101 of SEQ ID NO:21389 or its complement, wherein the presence of G at position 101 of SEQ ID NO:21389 or C at position 101 of its complement indicates said human has said increased risk for CHD. 
     
     
         2 . The method of  claim 1 , wherein said nucleic acid is a nucleic acid extract from a biological sample from said human. 
     
     
         3 . The method of  claim 2 , wherein said biological sample is blood, saliva, or buccal cells. 
     
     
         4 . The method of  claim 2 , further comprising preparing said nucleic acid extract from said biological sample prior to said testing. 
     
     
         5 . The method of  claim 4 , further comprising obtaining said biological sample from said human prior to said preparing. 
     
     
         6 . The method of  claim 1 , wherein said testing comprises nucleic acid amplification. 
     
     
         7 . The method of  claim 6 , wherein said nucleic acid amplification is carried out by polymerase chain reaction. 
     
     
         8 . The method of  claim 1 , further comprising correlating the presence of said G or said C with said increased risk for CHD. 
     
     
         9 . The method of  claim 8 , wherein said correlating is performed by computer software. 
     
     
         10 . The method of  claim 1 , further comprising correlating the absence of said G or said C with no said increased risk for CHD. 
     
     
         11 . The method of  claim 10 , wherein said correlating is performed by computer software. 
     
     
         12 . The method of  claim 1 , further comprising correlating the presence of said G or said C with a reduction of a likelihood of developing CHD by an HMG-CoA reductase inhibitor. 
     
     
         13 . The method of  claim 12 , wherein said correlating is performed by computer software. 
     
     
         14 . The method of  claim 12 , wherein said HMG-CoA reductase inhibitor is a hydrophilic statin. 
     
     
         15 . The method of  claim 12 , wherein said HMG-CoA reductase inhibitor is a hydrophobic statin. 
     
     
         16 . The method of  claim 12 , wherein said HMG-CoA reductase inhibitor is selected from the group consisting of pravastatin, atorvastatin, simvastatin, cerevastatin and lovastatin, or any combination thereof. 
     
     
         17 . 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). 
     
     
         18 . The method of  claim 1 , wherein said testing is performed using an allele-specific method. 
     
     
         19 . The method of  claim 18 , wherein said allele-specific method is allele-specific probe hybridization, allele-specific primer extension, or allele-specific amplification. 
     
     
         20 . The method of  claim 18 , wherein said allele-specific method is carried out using at least one allele-specific primer having a nucleotide sequence comprising SEQ ID NO:85538 or SEQ ID NO:85539. 
     
     
         21 . The method of  claim 18 , wherein said allele-specific method detects said G or said C. 
     
     
         22 . The method of  claim 1  which is an automated method. 
     
     
         23 - 41 . (canceled) 
     
     
         42 . A method of determining whether a human's risk for coronary heart disease (CHD) is reduced by treatment with an HMG-CoA reductase inhibitor, the method comprising testing nucleic acid from said human for the presence or absence of a polymorphism as represented by position 101 of SEQ ID NO:21389 or its complement, wherein the presence of G at position 101 of SEQ ID NO:21389 or C at position 101 of its complement indicates said human's risk for CHD is reduced by treatment with said HMG-CoA reductase inhibitor. 
     
     
         43 . The method of  claim 42 , further comprising correlating the presence of said G or said C with a reduction of said risk for CHD by an HMG-CoA reductase inhibitor. 
     
     
         44 . The method of  claim 42 , further comprising correlating the absence of said G or said C with no reduction of said risk for CHD by an HMG-CoA reductase inhibitor. 
     
     
         45 . A method for reducing risk of coronary heart disease (CHD) in a human, comprising administering to said human an effective amount of an HMG-CoA reductase inhibitor, wherein said human has been identified as having G at position 101 of SEQ ID NO:21389 or C at position 101 of its complement. 
     
     
         46 . The method of  claim 45 , wherein said method comprises testing nucleic acid from said human for the presence or absence of said G or said C. 
     
     
         47 . The method of  claim 1 , wherein said human is homozygous for said G or said C. 
     
     
         48 . (canceled) 
     
     
         49 . The method of  claim 42 , wherein said human is homozygous for said G or said C. 
     
     
         50 . The method of  claim 1 , wherein said human is heterozygous for said G or said C. 
     
     
         51 . (canceled) 
     
     
         52 . The method of  claim 42 , wherein said human is heterozygous for said G or said C. 
     
     
         53 . The method of  claim 1 , wherein said CHD is myocardial infarction. 
     
     
         54 . (canceled) 
     
     
         55 . The method of  claim 42 , wherein said CHD is myocardial infarction. 
     
     
         56 . A kit for carrying out the method of  claim 1 , the kit comprising a container and a reagent stored in said container, wherein said reagent is capable of detecting the presence or absence of said polymorphism.