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.

The FokI common variants in the VDR gene are associated with skeletal muscle strength in both patients and control subjects, whereas the BsmI polymorphism is associated with strength only in patients.