TCF7L2 in the Go-DARTS study:: evidence for a gene dose effect on both diabetes susceptibility and control of glucose levels

Aims/hypothesis The gene encoding transcription factor 7-like 2 (TCF7L2) has been identified as a type 2 diabetes locus from genome-wide linkage studies and subsequent association analysis. We investigated the role of two common variants in TCF7L2 in a large case-control study recruited from the Tayside region of Scotland, UK. Subjects and methods We genotyped 6,516 participants for rs12255372 and rs7903146 and analysed the role in type 2 diabetes susceptibility using binary logistic regression. Age, sex and obesity status were examined as covariates. The distribution of the genotypes within different treatment groups of cases was examined. Results Both variants were associated with type 2 diabetes (p<10(-13)). The variants were present at very similar frequencies and were in strong linkage disequilibrium (R-2=0.88, D'=0.89). A gene dosage effect of the rare allele of both variants was observed, the heterozygote CT group of rs7903146 having an odds ratio of 1.36 (95% CI 1.2-1.5, p = 1.54 x 10(-7)) for type 2 diabetes and the TT homozygote having a greater risk (OR=2.03, 95% CI 1.7-2.5, p = 1.40 x 10(-12)). An interaction with sex was observed, the males displaying a higher degree of genotype-associated risk compared with the females (p=0.023). The T allele was associated with increased HbA(1c) levels in both cases and controls, and with decreased BMI and waist circumference in case but not controls. The T allele was overrepresented in individuals requiring insulin treatment and underrepresented in the patients being managed by diet alone (p=0.006). Conclusions We have confirmed TCF7L2 to be a diabetes locus in a large case-control study in Tayside, UK. Our data suggest that variants of TCF7L2 may be associated with increased disease severity and therapeutic failure.