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.     

TCF7L2 polymorphisms are associated with type 2 diabetes in northern Sweden

A recent study found association of one microsatellite and five single nucleotide polymorphisms (SNPs) in intron 3 of the TCF7L2 gene with type 2 diabetes (T2D) in the Icelandic, Danish and American populations. The aim of the present study was to investigate if those SNPs were associated to T2D in two (family- and population-based) cohorts from northern Sweden. We genotyped four of the associated SNPs in a case-control cohort consisting of 872 T2D cases and 857 controls matched with respect to age, sex and geographical origin and in a sample of 59 extended families (148 affected and 83 unaffected individuals). Here, we report replication of association between T2D and three SNPs in the case-control (rs7901695, P=0.003; rs7901346, P=0.00002; and rs12255372, P=0.000004) and two SNPs in the family-based (rs7901695, P=0.01 and rs7901346, P=0.04) samples from northern Sweden. This replication strengthens the evidence for involvement of TCF7L2 in T2D.     

Type 2 diabetes gene TCF7L2 polymorphism is not associated with fetal and postnatal growth in two birth cohort studies

Background  

An inverse association between birth weight and the risk of developing type 2 diabetes (T2D) in adulthood has been reported. This association may be explained by common genetic variants related to insulin secretion and resistance, since insulin is the most important growth factor in fetal life. The objective of this study was to examine whether T2D gene polymorphism TCF7L2 rs7903146 is associated with growth patterns from fetal life until infancy.     

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.     

Replication of genetic variants from genome-wide association studies with metabolic traits in an island population of the Adriatic coast of Croatia

Twenty-two single-nucleotide polymorphisms (SNPs) in 10 gene regions previously identified in obesity and type 2 diabetes (T2D) genome-wide association studies (GWAS) were evaluated for association with metabolic traits in a sample from an island population of European descent. We performed a population-based study using 18 anthropometric and biochemical traits considered as continuous variables in a sample of 843 unrelated subjects (360 men and 483 women) aged 18-80 years old from the island of Hvar on the eastern Adriatic coast of Croatia. All eight GWAS SNPs in FTO were significantly associated with weight, body mass index, waist circumference and hip circumference; 20 of the 32 nominal P-values remained significant after permutation testing for multiple corrections. The strongest associations were found between the two TCF7L2 GWAS SNPs with fasting plasma glucose and HbA1c levels, all four P-values remained significant after permutation tests. Nominally significant associations were found between several SNPs and other metabolic traits; however, the significance did not hold after permutation tests. Although the sample size was modest, our study strongly replicated the association of FTO variants with obesity-related measures and TCF7L2 variants with T2D-related traits. The estimated effect sizes of these variants were larger or comparable to published studies. This is likely attributable to the homogenous genetic background of the relatively isolated study population.     

Association study of polymorphisms in miRNAs with T2DM in Chinese population

Accumulated evidence indicates that microRNA (miRNA or miR) is involved in the development of type 2 diabetes (T2DM). Several studies have shown that single nucleotide polymorphisms (SNPs) located in miRNAs are associated with T2DM in Caucasian populations. The association studies of miRNA''s SNPs with T2DM in Asian are rarely reported, and there are distinct genetic differences between Caucasian and Asian populations. The focus of this study, therefore, is the association of T2DM with five SNPs (rs895819 in miR-27a, rs531564 in miR-124a, rs11888095 in miR-128a, rs3820455 in miR-194a and rs2910164 in miR-146a) located in five miRNAs in a Han Chinese population. A total of 738 subjects with T2DM and 610 non-diabetic subjects were genotyped using the TaqMan method. Next, the associations between the five SNPs with T2DM and individual metabolic traits were evaluated. Our data showed that the C allele of rs531564 in miR-124a may protect against T2DM (P=0.009, OR=0.758; 95%CI: 0.616-0.933). Conversely, the C allele of rs2910164 in miR-146a may increase the risk of developing T2DM (P<0.001, OR=1.459; 95%CI: 1.244-1.712). However, these five SNPs did not exhibit significant associations with individual metabolic traits in either the T2DM or non-diabetic groups. Our results revealed that genetic variations in miRNAs were associated with T2DM susceptibility in a Han Chinese population, and these results highlight the need to study the functional effects of these variants in miRNAs on the risk of developing T2DM.