TCF7L2 is reproducibly associated with type 2 diabetes in various ethnic groups: a global meta-analysis

TCF7L2 variants have been consistently associated with type 2 diabetes (T2D) in populations of different ethnic descent. Among them, the rs7903146 T allele is probably the best proxy to evaluate the effect of this gene on T2D risk in additional ethnic groups. In the present study, we investigated the association between the TCF7L2 rs7903146 polymorphism and T2D in Moroccans (406 normoglycemic individuals and 504 T2D subjects) and in white Austrians (1,075 normoglycemic individuals and 486 T2D subjects). Then, we systematically reviewed the association of this single nucleotide polymorphism (SNP) with T2D risk in a meta-analysis, combining our data with data from previous studies. The allelic odds ratios (ORs) for T2D were 1.56 [1.29-1.89] (p = 2.9 x 10(-6)) and 1.52 [1.29-1.78] (p = 3.0 x 10(-7)) in Moroccans and Austrians, respectively. No heterogeneity was found between these two different populations by Woolf test (chi (2) = 0.04, df = 1, p = 0.84). We found 28 original published association studies dealing with the TCF7L2 rs7903146 polymorphism in T2D. A meta-analysis was then performed on 29,195 control subjects and 17,202 cases. No heterogeneity in genotypic distribution was found (Woolf test: chi (2) = 31.5, df = 26, p = 0.21; Higgins statistic: I2 = 14.1%). A Mantel-Haenszel procedure was then performed to provide a pooled odds ratio (OR) of 1.46 [1.42-1.51] (p = 5.4 x 10(-140)). No publication bias was detected, using the conservative Egger's regression asymmetry test (t = -1.6, df = 25, p = 0.11). Compared to any other gene variants previously confirmed by meta-analysis, TCF7L2 can be distinguished by its tremendous reproducibility of association with T2D and its OR twice as high. In the near future, large-scale genome-wide association studies will fully extend the genome coverage, potentially delivering other common diabetes-susceptibility genes like TCF7L2.     

A replication study of the IRS1, CAPN10, TCF7L2, and PPARG gene polymorphisms associated with type 2 diabetes in two different populations of Mexico

Type 2 diabetes (T2D) is a chronic degenerative disease that involves the participation of several genetic and environmental factors. The objective of the study was to determine the association of the IRS1 (rs1801278), CAPN10 (rs3792267), TCF7L2 (rs7903146 and rs12255372), and PPARG (rs1801282) gene polymorphisms with T2D, in two different Mexican populations. We conducted a case-control replication study in the state of Guerrero and in Mexico City, with 400 subjects from Guerrero and 1065 from Mexico City. Data were analyzed by logistic regression, adjusting by ancestry, age, gender, and BMI, to determine the association with T2D. Heterozygosity for the Gly972Arg variant of the IRS1 gene showed the strongest association for T2D in both analyzed samples (OR = 2.43, 95% CI 1.12-5.26 and 2.64, 95% CI 1.37-5.10, respectively). In addition, an association of two SNPs of the TCF7L2 gene with T2D was observed in both cities: rs7903146, (for Guerrero OR = 1.98 CI95% 1.02-3.89 and for Mexico OR = 1.94 CI95% 1.31-2.88) and rs12255372 (OR = 1.79 CI95% 1.08-2.97, OR = 1.78 CI95% 1.17-2.71 respectively). We suggest that our results provide strong evidence that variation in the IRS1 and TCF7L2 genes confers susceptibility to T2D in our studied populations.     

A Validation Study of Type 2 Diabetes‐related Variants of the TCF7L2, HHEX,KCNJ11, and ADIPOQ Genes in one Endogamous Ethnic Group of North India

The aim of this study was to validate the single nucleotide polymorphisms (SNPs) of four candidate genes (TCF7L2, HHEX, KCNJ11, and ADIPOQ) related to type 2 diabetes (T2D) in an endogamous population of north India; the Aggarwal population, having 18‐clans. This endogamous population model was heavily supported by recent land mark work and we also verified the homogeneity of this population by clan‐based stratification analysis. Two SNPs (rs4506565; rs7903146) in TCF7L2 were found to be significant (p‐value = 0.00191; p‐value = 0.00179, respectively), and odds ratios of 2.1 (dominant‐model) and 2.0 (recessive‐model) respectively, were obtained for this population. The TTT haplotype in the TCF7L2 gene was significantly associated with T2D. Waist‐Hip ratio (WHR), systolic blood pressure (SBP), and age were significant covariates for increasing risk of T2D. Single‐SNP, combined‐SNPs and haplotype analysis provides clear evidence that the causal mutation is near to or within the significant haplotype (TTT) of the TCF7L2 gene. In spite of a culturally‐learned sedentary lifestyle and fat‐enriched dietary habits, WHR rather than body‐mass‐index emerged as a robust predictor of risk for T2D in this population.     

Weak or no association of <Emphasis Type="Italic">TCF7L2</Emphasis> variants with Type 2 diabetes risk in an Arab population

Background  

The rs7903146 and rs12255372 variants of TCF7L2 have been strongly associated with type 2 diabetes (T2D) risk in most populations studied to date. Meta-analysis of 27 different studies has resulted in a global OR of 1.46 [1.42–1.51] (rs7903146 variant). Thus far, despite a high incidence of T2D, the role of this variant in Arabs has not been established.     

<Emphasis Type="Italic">TCF7L2</Emphasis>variant genotypes and type 2 diabetes risk in Brazil: significant association,but not a significant tool for risk stratification in the general population

Background  

Genetic polymorphisms of the TCF7L2 gene are strongly associated with large increments in type 2 diabetes risk in different populations worldwide. In this study, we aimed to confirm the effect of the TCF7L2 polymorphism rs7903146 on diabetes risk in a Brazilian population and to assess the use of this genetic marker in improving diabetes risk prediction in the general population.     

<Emphasis Type="Italic">TCF7L2</Emphasis> rs7903146 variant does not associate with smallness for gestational age in the French population

Background  

In adults, the TCF7L2 rs7903146 T allele, commonly associated with type 2 diabetes (T2D), has been also associated with a lower body mass index (BMI) in T2D individuals and with a smaller waist circumference in subjects with impaired glucose tolerance.     

Genome-wide association scan allowing for epistasis in type 2 diabetes

In the presence of epistasis multilocus association tests of human complex traits can provide powerful methods to detect susceptibility variants. We undertook multilocus analyses in 1924 type 2 diabetes cases and 2938 controls from the Wellcome Trust Case Control Consortium (WTCCC). We performed a two‐dimensional genome‐wide association (GWA) scan using joint two‐locus tests of association including main and epistatic effects in 70,236 markers tagging common variants. We found two‐locus association at 79 SNP‐pairs at a Bonferroni‐corrected P‐value = 0.05 (uncorrected P‐value = 2.14 × 10^?11). The 79 pair‐wise results always contained rs11196205 in TCF7L2 paired with 79 variants including confirmed variants in FTO, TSPAN8, and CDKAL1, which are associated in the absence of epistasis. However, the majority (82%) of the 79 variants did not have compelling single‐locus association signals (P‐value = 5 × 10^?4). Analyses conditional on the single‐locus effects at TCF7L2 established that the joint two‐locus results could be attributed to single‐locus association at TCF7L2 alone. Interaction analyses among the peak 80 regions and among 23 previously established diabetes candidate genes identified five SNP‐pairs with case‐control and case‐only epistatic signals. Our results demonstrate the feasibility of systematic scans in GWA data, but confirm that single‐locus association can underlie and obscure multilocus findings.