TCF7L2 in the Go-DARTS study: evidence for a gene dose effect on both diabetes susceptibility and control of glucose levels.
Kimber CH., Doney AS., Pearson ER., McCarthy MI., Hattersley AT., Leese GP., Morris AD., Palmer CN.
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.