Association between TCF7L2 gene polymorphisms and susceptibility to Type 2 Diabetes Mellitus: a large Human Genome Epidemiology (HuGE) review and meta-analysis

Open laboratory, West China Second University Hospital, Sichuan University, Chengdu, PR China.
BMC Medical Genetics (Impact Factor: 2.45). 02/2009; 10(1). DOI: 10.1186/1471-2350-10-15
Source: DOAJ

ABSTRACT 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.

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.

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 ORs 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 ORs 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.

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.

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    ABSTRACT: Previous studies showed associations between variants in TCF7L2 gene and the therapeutic response to sulfonylureas. All sulfonylureas stimulate insulin secretion by the closure of ATP-sensitive potassium (KATP) channel. The aim of the present study was to compare TCF7L2 genotype specific effect of gliclazide binding to KATP channel A-site (Group 1) with sulfonylureas binding to AB-site (Group 2). A total of 101 patients were treated with sulfonylureas for 6 months as an add-on therapy to the previous metformin treatment. TCF7L2 rs7903146 C/T genotype was identified by real-time PCR with subsequent melting curve analysis. Analyses using the dominant genetic model showed significantly higher effect of gliclazide in the CC genotype group in comparison with combined CT + TT genotype group (1.32 ± 0.15% versus 0.73 ± 0.11%, P (adj) = 0.005). No significant difference in ΔHbA1c between the patients with CC genotype and the T-allele carriers was observed in Group 2. In the multivariate analysis, only the TCF7L2 genotype (P = 0.006) and the baseline HbA1c (P < 0.001) were significant predictors of ΔHbA1c. After introducing an interaction term between the TCF7L2 genotype and the sulfonylurea type into multivariate model, the interaction became a significant predictor (P = 0.023) of ΔHbA1c. The results indicate significantly higher difference in ΔHbA1c among the TCF7L2 genotypes in patients treated with gliclazide than in patients treated with glimepiride, glibenclamide, or glipizide.
    International Journal of Endocrinology 01/2013; 2013:374858. DOI:10.1155/2013/374858 · 1.52 Impact Factor
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    ABSTRACT: In various populations worldwide, common variants of the TCF7L2 (Transcription factor 7-like 2) gene are associated with the risk of type 2 diabetes mellitus (T2DM). The aim was to investigate the association between rs12255372 (G/T) polymorphism in the TCF7L2 gene and T2DM in an Iranian population. 236 unrelated patients with T2DM, and 255 normoglycemic controls without diabetes were studied. The PCR-RFLP method was used for genotyping rs12255372 (G/T) polymorphism, and the SPSS version 18.0 for Windows for statistical analysis. The minor T allele of TCF7L2 rs12255372 was found to significantly increase the risk of T2DM, with an allelic odds ratio (OR) of 1.458 (95% CI 1.108-1.918, p = 0.007). A significant difference in TT genotype was observed between T2DM patients and normoglycemic controls (OR 2.038, 95% CI 1.147-3.623; p = 0.014). On assuming dominant and recessive models, ORs of 1.52 [95% CI (1.05-2.21) p = 0.026)] and 1.74 [95% CI (1.01-3.00) p = 0.043] were obtained, respectively, thereby implying that the co-dominant model would best fit the susceptible gene effect. This study further confirms the TCF7L2 gene as enhancing susceptibility to the development of T2DM.
    Genetics and Molecular Biology 04/2012; 35(2):413-7. DOI:10.1590/S1415-47572012005000029 · 0.88 Impact Factor


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