Common variants in the TCF7L2 gene and predisposition to type 2 diabetes in UK European Whites, Indian Asians and Afro-Caribbean men and women

Abstract

Common variants of TCF7L2, encoding a beta-cell-expressed transcription factor, are strongly associated with increased risk of type 2 diabetes (T2D). We examined this association using both prospective and case-control designs. A total of 2,676 healthy European white middle-aged men from the prospective NPHSII (158 developed T2D over 15 years surveillance) were genotyped for two intronic SNPs [rs 7903146 (IVS3C>T) and rs12255372 (IVS4G>T)] which showed strong linkage disequilibrium (D' = 0.88, p<0.001; R(2)=0.76, p<0.001). The IVS5T allele frequency was 0.28 (95% CI 0.27-0.29) and 0.33 (0.28-0.39) in healthy and T2D, respectively (p=0.04). Compared to CC men, CT and TT men had an adjusted [for age, body mass index, systolic blood pressure, triglyceride and C-reactive protein levels] hazard ratio for T2D of 1.65 (1.13-2.41) and 1.87 (0.99-3.53), respectively, p<0.01. The population attributable fraction for diabetes risk was 17%. In 1459, European white T2D men and women (60% male), T allele frequency was 0.36 (0.34-0.38), and compared to NPHSII healthy men the OR for T2D for the CT and TT subjects was 1.43 (1.24-1.65) and 2.11 (1.69-2.63), respectively p=<0.0001. A similar effect was observed in 919 T2D Indian Asians [OR=1.50 (1.14-1.99) and 1.64 (1.03-2.63) p=0.003] and 385 Afro-Caribbean subjects [OR=1.25 (0.90-1.75) and 1.32 (0.74-2.33) p=0.17] compared to non-diabetic ethnically matched subjects from South London. Weaker associations were found for the IVS4G>T in all studies. Linkage disequilibrium between the two SNPs was high in Indian Asians (D'=0.94), but much weaker in Afro-Caribbeans (D'=0.17) and haplotype frequencies differed markedly in this group. These results extend previous observations to other ethnic groups, and strongly confirm that TCF7L2 genotype is a major risk factor for development of T2D.

A genetic variation of the transcription factor 7-like 2 gene is associated with risk of type 2 diabetes in the Japanese population

“…It is noteworthy that the association between the SNP in TCF7L2 and type 2 diabetes has consistently been observed in different ethnic groups [14,15], which supports the reliability of both previous studies as well as our present study. The mechanism of action of TCF7L2 in glucose metabolism and the pathogenesis of type 2 diabetes has yet to be elucidated, but it is possible that TCF7L2 has a role in regulating glucose-sensitive insulin secretion from beta cells.…”

Association Study of the Genetic Polymorphisms of the Transcription Factor 7-Like 2 (TCF7L2) Gene and Type 2 Diabetes in the Chinese Population

“…Five single nucleotide polymorphisms (SNPs) (rs12255372, rs7903146, rs7901695, rs11196205, and rs7895340) within the LD block also showed similarly robust associations with type 2 diabetes (6). Further studies in other European populations, African Americans, Mexican Americans, and Asian Indians confirmed the strong associations with an estimated population attributable risk of 17-28% (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22). Several genome-wide association studies independently confirmed the strong associations of SNP rs7903146 in the TCF7L2 locus with type 2 diabetes (23)(24)(25)(26).…”

TCF7L2 single nucleotide polymorphisms, cardiovascular disease and all-cause mortality: the Atherosclerosis Risk in Communities (ARIC) study

“…Polymorphisms of TCF7L2 have been associated with diabetes in numerous studies [1][2][3] and the magnitude of risk conferred by TCF7L2 variants is greater than for any previously described common variant. The single nucleotide polymorphism (SNP) rs7903146 is the most highly associated of the known variants and is associated with a 40% increased risk of diabetes per allele [4].…”