Genetic variants in the TCF7L2 gene as diagnostic markers for risk of type 2 diabetes mellitus

Abstract

Polymorphisms in the gene TCF7L2 are shown by association analysis to be a susceptibility gene for type II diabetes. Methods of diagnosis of susceptibility to diabetes, of decreased susceptibility to diabetes and protection against diabetes, are described, as are methods of treatment for type II diabetes.

1 . A method of diagnosing an increased susceptibility to type II diabetes in an individual, comprising detecting a marker or haplotype associated with the exon 4 LD block of TCF7L2 in the individual, wherein the presence of the marker or haplotype is indicative of an increased susceptibility to type II diabetes. 
     
     
         2 . The method of  claim 1 , wherein the marker or haplotype comprises at least one marker selected from the markers listed in Table 6. 
     
     
         3 . The method of  claim 1 , wherein the increased susceptibility is characterized by a relative risk of at least 1.2. 
     
     
         4 . A method of assessing an individual for probability of response to a TCF7L2 therapeutic agent, comprising: detecting a marker associated with the exon 4 LD block of TCF7L2, wherein the presence of the marker is indicative of a probability of a positive response to a TCF7L2 therapeutic agent. 
     
     
         5 . The method of  claim 4 , wherein the marker is selected from the group consisting of DG10S478, rs12255372, rs7895340, rs11196205, rs7901695, rs7903146, rs12243326, and rs4506565. 
     
     
         6 . The method of  claim 5 , wherein the marker is marker DG10S478, and wherein the presence of a non-0 allele in DG10S478 is indicative of a probability of a positive response to a TCF7L2 therapeutic agent. 
     
     
         7 . The method of  claim 5 , wherein the marker is marker rs7903146, and wherein the presence of a T allele in rs7903146 is indicative of a probability of a positive response to a TCF7L2 therapeutic agent. 
     
     
         8 . A method of diagnosing a decreased susceptibility to type II diabetes in an individual, comprising detecting a marker or haplotype associated with the exon 4 LD block of TCF7L2 in the individual, wherein the presence of the marker or haplotype is indicative of a decreased susceptibility to type II diabetes. 
     
     
         9 . The method of  claim 8 , wherein the decreased susceptibility is characterized by a relative risk of less than 0.8. 
     
     
         10 . A method of detecting an increased susceptibility to type II diabetes in an individual, comprising identifying the presence or absence of an allele at a marker associated with the exon 4 LD block of TCF7L2 in the individual, wherein identification of the presence of the allele is indicative of increased susceptibility to type II diabetes in the individual. 
     
     
         11 . The method of  claim 10 , wherein the marker associated with the exon 4 LD block of TCF7L2 is a marker in strong linkage disequilibrium, characterized by r 2  greater than 0.2, with the exon 4 LD block of TCF7L2. 
     
     
         12 . The method of  claim 10 , wherein the marker associated with the exon 4 LD block of TCF7L2 is a marker in strong linkage disequilibrium, characterized by r 2  greater than 0.2, with one or more of the markers listed in Table 6. 
     
     
         13 . The method of  claim 10 , wherein the marker associated with the exon 4 LD block of TCF7L2 is selected from the group consisting of the markers listed in Table 6. 
     
     
         14 . A method of detecting a decreased susceptibility to type II diabetes in an individual, comprising identifying the presence or absence of an allele at a marker associated with the exon 4 LD block of TCF7L2 in the individual, wherein identification of the presence of the allele is indicative of decreased susceptibility to type II diabetes in the individual. 
     
     
         15 . The method of  claim 14 , wherein the marker associated with the exon 4 LD block of TCF7L2 is a marker in strong linkage disequilibrium, characterized by r 2  greater than 0.2, with the exon 4 LD block of TCF7L2. 
     
     
         16 . The method of  claim 14 , wherein the marker associated with the exon 4 LD block of TCF7L2 is a marker in strong linkage disequilibrium, characterized by r 2  greater than 0.2, with one or more of the markers listed in Table 6. 
     
     
         17 . The method of  claim 14 , wherein the marker associated with the exon 4 LD block of TCF7L2 is selected from the group consisting of the markers listed in Table 6. 
     
     
         18 . A method of detecting an increased susceptibility to type II diabetes in an individual, comprising detecting an allele at a polymorphism associated with the exon 4 LD block of TCF7L2 in the individual, wherein identification of said allele at the polymorphism is indicative of increased risk of type II diabetes in the individual. 
     
     
         19 . The method of  claim 18 , wherein the marker associated with the exon 4 LD block of TCF7L2 is a marker in strong linkage disequilibrium, characterized by r 2  greater than 0.2, with the exon 4 LD block of TCF7L2. 
     
     
         20 . The method of  claim 18 , wherein the marker associated with the exon 4 LD block of TCF7L2 is a marker in strong linkage disequilibrium, characterized by r 2  greater than 0.2, with one or more of the markers listed in Table 6. 
     
     
         21 . The method of  claim 18 , wherein the marker associated with the exon 4 LD block of TCF7L2 is selected from the group consisting of the markers listed in Table 6. 
     
     
         22 . A method of detecting a decreased susceptibility to type II diabetes in an individual, comprising detecting an allele at a polymorphism associated with the exon 4 LD block of TCF7L2 in the individual, wherein identification of said allele at the polymorphism is indicative of decreased risk of type II diabetes in the individual. 
     
     
         23 . The method of  claim 22 , wherein the marker associated with the exon 4 LD block of TCF7L2 is a marker in strong linkage disequilibrium, characterized by r 2  greater than 0.2, with the exon 4 LD block of TCF7L2. 
     
     
         24 . The method of  claim 22 , wherein the marker associated with the exon 4 LD block of TCF7L2 is a marker in strong linkage disequilibrium, characterized by r 2  greater than 0.2, with one or more of the markers listed in Table 6. 
     
     
         25 . The method of  claim 22 , wherein the marker associated with the exon 4 LD block of TCF7L2 is selected from the group consisting of the markers listed in Table 6.