Genetic polymorphisms associated with venous thrombosis, methods of detection and uses thereof

Abstract

The present invention is based on the discovery of genetic polymorphisms that are associated with coronary heart disease and in particular VT and response to drug treatment. 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 a human who has an altered risk for developing venous thrombosis (VT), comprising detecting a single nucleotide polymorphism (SNP) as specified in any one of the nucleotide sequences of SEQ ID NOs: 41-68 and 82-199 or a complement thereof, in said human's nucleic acids, wherein the presence of the SNP is indicative of an altered risk for VT in said human. 
     
     
         2 . The method of  claim 1  in which the altered risk is an increased risk. 
     
     
         3 . The method of  claim 1  in which the altered risk is a decreased risk. 
     
     
         4 . The method of  claim 1  in which the detecting 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. 
     
     
         5 . A method for identifying a human who has an altered risk for developing venous thrombosis (VT), comprising detecting a first single nucleotide polymorphism (SNP) which is in linkage disequilibrium (LD) with a second SNP as specified in any one of the nucleotide sequences of SEQ ID NOs: 41-68 and 82-199 or a complement thereof, in said human's nucleic acids, wherein the presence of said first SNP is indicative of an altered risk for VT in said human. 
     
     
         6 . The method of  claim 5  in which the altered risk is an increased risk. 
     
     
         7 . The method of  claim 5  in which the altered risk is a decreased risk. 
     
     
         8 . The method of  claim 5  in which the detecting 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 . A method for identifying an agent useful in therapeutically or prophylactically treating venous thrombosis (VT), comprising contacting a polypeptide comprising an amino acid sequence encoded by any one of the nucleotide sequences of SEQ ID NOs: 41-68 and 82-199 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. 
     
     
         10 . The method of  claim 9  wherein the amino acid sequence is selected from the group consisting of SEQ ID NOs: 21-40. 
     
     
         11 . The method of  claim 9  wherein said agent comprises a chemical entity. 
     
     
         12 . The method of  claim 9  wherein said agent comprises an antibody that specifically binds to the polypeptide. 
     
     
         13 . A method for identifying a human who is in need of receiving treatment for venous thrombosis (VT), comprising detecting a single nucleotide polymorphism (SNP) as specified in any one of the nucleic acid sequences of SEQ ID NOs: 41-68 and 82-199, in a sample from said human, and treating said human with a therapeutic agent. 
     
     
         14 . The method of  claim 13  wherein said therapeutic agent comprises a chemical entity. 
     
     
         15 . The method of  claim 13  wherein said therapeutic agent comprises an antibody. 
     
     
         16 . A kit for identifying a human who has an altered risk for developing venous thrombosis (VT) by detecting a SNP in a SNP-containing nucleic acid molecule comprising a primer and a probe, wherein the probe selectively hybridizes to the SNP-containing nucleic acid molecule as compared to hybridization to a nucleic acid molecule which does not contain the SNP at the same nucleotide position, wherein the SNP is in any one of the nucleotide sequences of SEQ ID NOs: 41-68 and SEQ ID NOS: 82-199. 
     
     
         17 . The kit of  claim 16  in which the altered risk is an increased risk. 
     
     
         18 . The kit of  claim 16  in which the altered risk is a decreased risk. 
     
     
         19 . The kit of  claim 16  in which the detecting 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. 
     
     
         20 . The kit of  claim 16  further comprising a buffer.