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 a susceptibility to type II diabetes in an individual, comprising analyzing at least one allele of at least one marker associated with the exon 4 LD block of Transcription Factor 7-Like 2 Gene (TCF7L2) in nucleic acid from the individual,
 wherein the at least one marker is selected from the group consisting of
 DG10S478, rs12255372, rs7895340, rs11196205, rs7901695, rs7903146, rs12243326, rs4506565, and 
 markers in linkage disequilibrium, characterized by r 2  greater than 0.2, with any of said markers; and 
   diagnosing a susceptibility to type II diabetes in the individual from the presence or absence of the at least one allele, wherein the presence of an at-risk allele for the at least one marker in the nucleic acid is indicative of an increased susceptibility to type II diabetes, and the absence of an at-risk allele is indicative of a decreased susceptibility to type II diabetes.   
     
     
         2 . The method of  claim 1 , wherein the at least one marker comprises at least one marker selected from the group consisting of rs4074720, rs4074719, rs4074718, rs11196181, rs11196182, rs4603236, rs7922298, rs17747324, rs7901695, rs11196185, rs4132115, rs4506565, rs7068741, rs7069007, rs7903146, rs11196187, rs7092484, rs10885402, rs12098651, rs6585198, rs7910244, rs12266632, rs6585199, rs7896811, rs6585200, rs6585201, rs4319449, rs12220336, rs7896091, rs12354626, rs7075199, rs7904519, rs13376896, rs10885405, rs10885406, rs11196192, rs6585202, rs7924080, rs7907610, rs12262948, rs12243326, rs12265110, rs7077039, rs11196198, rs12775336, rs7904948, rs7100927, rs11196199, rs17685538, rs11592706, rs7081912, rs7895340, rs11196200, rs11196201, rs11196202, rs11196203, rs11196204, rs11196205, rs10885409, rs12255372, rs12265291, rs7904443, rs11196208, rs7077247, rs11196209, rs4077527, rs12718338, rs11196210, rs7907632, rs7071302, rs12245680, rs11196213, rs4918789, rs7085785, rs7085989, rs7087006, SG10S405, SG10S428, SG10S422, SG10S427, SG10S408, SG10S409, SG10S406, SG10S407, DG10S2164, DG10S478, and DG10S479. 
     
     
         3 . The method of  claim 1 , wherein the susceptibility is an increased susceptibility characterized by a relative risk of at least 1.2. 
     
     
         4 . (canceled) 
     
     
         5 . The method of  claim 1 , wherein the marker is selected from the group consisting of DG10S478, rs12255372, rs7895340, rs11196205, rs7901695, rs7903146, rs12243326, and rs4506565. 
     
     
         6 . The method of  claim 1 , wherein the marker is marker DG10S478, or a marker in linkage disequilibrium with DG10S478, characterized by an r 2  greater than 0.2, and wherein the presence of a non-0 allele in DG10S478 is indicative of increased susceptibility to type II diabetes. 
     
     
         7 . The method of  claim 1 , wherein the marker is marker rs7903146, or a marker in linkage disequilibrium with rs7903146, characterized by an r 2  greater than 0.2, and wherein the presence of a T allele in rs7903146 is indicative of increased susceptibility to type II diabetes. 
     
     
         8 . The method according to  claim 1  of diagnosing a decreased susceptibility to type II diabetes in an individual, comprising detecting absence of the at-risk allele, wherein the absence of the at-risk allele 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 . (canceled) 
     
     
         11 . (canceled) 
     
     
         12 . (canceled) 
     
     
         13 . (canceled) 
     
     
         14 . (canceled) 
     
     
         15 . (canceled) 
     
     
         16 . (canceled) 
     
     
         17 . (canceled) 
     
     
         18 . A method according to  claim 1  of detecting an increased susceptibility to type II diabetes in an individual, comprising detecting an allele of at least one marker located within the exon 4 LD block of TCF7L2 in the individual, wherein identification of said allele at the polymorphism that is indicative of increased risk of type II diabetes in the individual. 
     
     
         19 . (canceled) 
     
     
         20 . (canceled) 
     
     
         21 . The method of  claim 18 , wherein the at least one marker is selected from the group consisting of rs4074720, rs4074719, rs4074718, rs11196181, rs11196182, rs4603236, rs7922298, rs17747324, rs7901695, rs11196185, rs4132115, rs4506565, rs7068741, rs7069007, rs7903146, rs11196187, rs7092484, rs10885402, rs12098651, rs6585198, rs7910244, rs12266632, rs6585199, rs7896811, rs6585200, rs6585201, rs4319449, rs12220336, rs7896091, rs12354626, rs7075199, rs7904519, rs13376896, rs10885405, rs10885406, rs11196192, rs6585202, rs7924080, rs7907610, rs12262948, rs12243326, rs12265110, rs7077039, rs11196198, rs12775336, rs7904948, rs7100927, rs11196199, rs17685538, rs11592706, rs7081912, rs7895340, rs11196200, rs11196201, rs11196202, rs11196203, rs11196204, rs11196205, rs10885409, rs12255372, rs12265291, rs7904443, rs11196208, rs7077247, rs11196209, rs4077527, rs12718338, rs11196210, rs7907632, rs7071302, rs12245680, rs11196213, rs4918789, rs7085785, rs7085989, rs7087006, SG10S405, SG10S428, SG10S422, SG10S427, SG10S408, SG10S409, SG10S406, SG10S407, DG10S2164, DG10S478, and DG10S479. 
     
     
         22 . The method according to  claim 1  of diagnosing a decreased susceptibility to type II diabetes in an individual, comprising detecting absence of the at-risk allele located within the exon 4 LD block of TCF7L2 wherein the absence of the at-risk allele is indicative of decreased risk of type II diabetes in the individual. 
     
     
         23 . (canceled) 
     
     
         24 . (canceled) 
     
     
         25 . The method of  claim 22 , wherein the at least one marker is selected from the group consisting of rs4074720, rs4074719, rs4074718, rs11196181, rs11196182, rs4603236, rs7922298, rs17747324, rs7901695, rs11196185, rs4132115, rs4506565, rs7068741, rs7069007, rs7903146, rs11196187, rs7092484, rs10885402, rs12098651, rs6585198, rs7910244, rs12266632, rs6585199, rs7896811, rs6585200, rs6585201, rs4319449, rs12220336, rs7896091, rs12354626, rs7075199, rs7904519, rs13376896, rs10885405, rs10885406, rs11196192, rs6585202, rs7924080, rs7907610, rs12262948, rs12243326, rs12265110, rs7077039, rs11196198, rs12775336, rs7904948, rs7100927, rs11196199, rs17685538, rs11592706, rs7081912, rs7895340, rs11196200, rs11196201, rs11196202, rs11196203, rs11196204, rs11196205, rs10885409, rs12255372, rs12265291, rs7904443, rs11196208, rs7077247, rs11196209, rs4077527, rs12718338, rs11196210, rs7907632, rs7071302, rs12245680, rs11196213, rs4918789, rs7085785, rs7085989, rs7087006, SG10S405, SG10S428, SG10S422, SG10S427, SG10S408, SG10S409, SG10S406, SG10S407, DG10S2164, DG10S478, and DG10S479.