Association between TCF7L2 gene polymorphisms and susceptibility to type 2 diabetes mellitus: a large Human Genome Epidemiology (HuGE) review and meta-analysis. BMC Med Genet 10:15

Open laboratory, West China Second University Hospital, Sichuan University, Chengdu, PR China.
BMC Medical Genetics (Impact Factor: 2.08). 02/2009; 10(1). DOI: 10.1186/1471-2350-10-15
Source: PubMed


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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    • "TCF7L2 (transcription factor 7-like-2) has been previously linked to T2D, and has been cited as one of the most important signals associated with T2D[51]. The T allele was identified as a diabetes risk factor in the pre-GWAS era and was later replicated across a number of groups with different ethnic ancestry[52,53]. It is not yet completely understood how TCF7L2 influences risk of T2D but a number of theories have been put forward. "
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    ABSTRACT: Purpose: New onset diabetes after transplantation (NODAT) is a serious complication following solid organ transplantation. There is a genetic contribution to NODAT and we have conducted comprehensive meta-analysis of available genetic data in kidney transplant populations. Methods: Relevant articles investigating the association between genetic markers and NODAT were identified by searching PubMed, Web of Science and Google Scholar. SNPs described in a minimum of three studies were included for analysis using a random effects model. The association between identified variants and NODAT was calculated at the per-study level to generate overall significance values and effect sizes. Results: Searching the literature returned 4,147 citations. Within the 36 eligible articles identified, 18 genetic variants from 12 genes were considered for analysis. Of these, three were significantly associated with NODAT by meta-analysis at the 5% level of significance; CDKAL1 rs10946398 p = 0.006 OR = 1.43, 95% CI = 1.11-1.85 (n = 696 individuals), KCNQ1 rs2237892 p = 0.007 OR = 1.43, 95% CI = 1.10-1.86 (n = 1,270 individuals), and TCF7L2 rs7903146 p = 0.01 OR = 1.41, 95% CI = 1.07-1.85 (n = 2,967 individuals). Conclusion: Evaluating cumulative evidence for SNPs associated with NODAT in kidney transplant recipients has revealed three SNPs associated with NODAT. An adequately powered, dense genome-wide association study will provide more information using a carefully defined NODAT phenotype.
    Full-text · Article · Jan 2016 · PLoS ONE
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    • "Genome-wide association studies have identified several susceptibility genes for developing type 2 diabetes.[92] Polymorphisms in the transcription factor 7-like 2 (TCF-7L2) gene have been shown to be strongly associated with increasing risk of developing type 2 diabetes in populations of various ethnicities including Asians.[9394] Hypothetically speaking, the TCF-7L2 polymorphisms can augment the onset of MODY at an earlier age or modify its clinical expression. "
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    ABSTRACT: Diabetes is highly prevalent in India and the proportion of younger patients developing diabetes is on the increase. Apart from the more universally known type 1 diabetes and obesity related type 2 diabetes, monogenic forms of diabetes are also suspected to be prevalent in many young diabetic patients. The identification of the genetic basis of the disease not only guides in therapeutic decision making, but also aids in genetic counselling and prognostication. Genetic testing may establish the occurrence and frequency of early diabetes in our population. This review attempts to explore the utilities and horizons of molecular genetics in the field of maturity onset diabetes of the young (MODY), which include the commoner forms of monogenic diabetes.
    Full-text · Article · May 2013
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    • "A number of epidemiological studies have evaluated the association between rs12255372 and T2DM, but the results remain conflicting rather than conclusive 2-34; see Table 1). Two meta-analyses on the association between the TCF7L2 polymorphism rs12255372 and T2DM have been published 35, 36. The first, published in 2009, detected significant associations between 4 single nucleotide polymorphisms (SNPs: rs7903146, rs12255372, rs7901695, and rs11196205) in TCF7L2 and T2DM all over the world 35; however, only articles published before 2008 were included. "
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    ABSTRACT: Our objective was to evaluate the association of rs12255372 in the TCF7L2 gene with type 2 diabetes mellitus (T2DM) in the world population. We carried out a survey of the literature about the effect of rs12255372 on genetic susceptibility to T2DM by consulting PubMed, the Cochrane Library, and Embase from 2006 to 2012, and then performed a meta-analysis of all the studies in order to evaluate the association between rs12255372 and T2DM. A total of 33 articles including 42 studies (with 34,076 cases and 36,192 controls) were confirmed to be eligible and were included in the final meta-analysis: 6 studies conducted on Europeans, 14 on Caucasians, 17 on Asians, 2 on Africans, and 3 on Americans. Overall, the effect size was as follows: for the variant allele T (OR = 1.387, 95%CI = 1.351-1.424), for the TT genotype (OR = 1.933, 95%CI = 1.815-2.057), for the GT genotype (OR = 1.363, 95%CI = 1.315-1.413), for the dominant model (OR = 1.425, 95%CI = 1.344-1.510), and for the recessive model (OR = 1.659, 95%CI = 1.563-1.761). In summary, by pooling all available qualified data from genetic studies on rs12255372 and T2DM, we have confirmed that rs12255372 is significantly associated with susceptibility to T2DM in the global population.
    Full-text · Article · Apr 2013 · Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas / Sociedade Brasileira de Biofisica ... [et al.]
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