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Background  Transcription factor 7-like 2 ( TCF7L2 ) has been shown to be associated with type 2 diabetes mellitus (T2MD) in multiple ethnic groups in the past two years, but, contradictory results were reported for Chinese and Pima Indian populations. The authors then performed a large meta-analysis of 36 studies examining the association of type 2 diabetes mellitus (T2DM) with polymorphisms in the  TCF7L2  gene in various ethnicities, containing rs7903146 C-to-T (IVS3C>T), rs7901695 T-to-C (IVS3T>C), a rs12255372 G-to-T (IVS4G>T), and rs11196205 G-to-C (IVS4G>C) polymorphisms and to evaluate the size of gene effect and the possible genetic mode of action.    Methods  Literature-based searching was conducted to collect data and three methods, that is, fixed-effects, random-effects and Bayesian multivariate mete-analysis, were performed to pool the odds ratio ( OR ). Publication bias and study-between heterogeneity were also examined.    Results  The studies included 35,843 cases of T2DM and 39,123 controls, using mainly primary data. For T2DM and IVS3C>T polymorphism, the Bayesian  OR  for TT homozygotes and TC heterozygotes versus CC homozygote was 1.968 (95% credible interval ( CrI ): 1.790, 2.157), 1.406 (95%  CrI : 1.341, 1.476), respectively, and the population attributable risk (PAR) for the TT/TC genotypes of this variant is 16.9% for overall. For T2DM and IVS4G>T polymorphism, TT homozygotes and TG heterozygotes versus GG homozygote was 1.885 (95% CrI : 1.698, 2.088), 1.360 (95%  CrI : 1.291, 1.433), respectively. Four  OR s among these two polymorphisms all yielded significant between-study heterogeneity (P < 0.05) and the main source of heterogeneity was ethnic differences. Data also showed significant associations between T2DM and the other two polymorphisms, but with low heterogeneity ( P  > 0.10). Pooled  OR s fit a codominant, multiplicative genetic model for all the four polymorphisms of  TCF7L2  gene, and this model was also confirmed in different ethnic populations when stratification of IVS3C>T and IVS4G>T polymorphisms except for Africans, where a dominant, additive genetic mode is suggested for IVS3C>T polymorphism.    Conclusion  This meta-analysis demonstrates that four variants of  TCF7L2  gene are all associated with T2DM, and indicates a multiplicative genetic model for all the four polymorphisms, as well as suggests the  TCF7L2  gene involved in near 1/5 of all T2MD. Potential gene-gene and gene-environmental interactions by which common variants in the  TCF7L2  gene influence the risk of T2MD need further exploration.

bmc medical genetics

Association between TCF7L2gene polymorphisms and susceptibility to Type 2 Diabetes Mellitus: a large Human Genome Epidemiology (HuGE) review and meta-analysis