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 × 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 × 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 HbA1c 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. © 2007 Springer-Verlag.