TCF7L2 Variation Predicts Hyperglycemia Incidence in a French General Population

Abstract

,7 for the DESIR Study Group 2 * Recently, case-control studies demonstrated that a TCF7L2 (transcription factor 7-like 2 gene) noncoding variant (rs7903146 T at-risk allele) was strongly associated with an increased risk of type 2 diabetes. However, the predictive value of this marker in a nonselected general population remains unknown. In this study, our aim was to assess the contribution of this variant to the prevalence and incidence of hyperglycemia (type 2 diabetes and impaired fasting glucose) and insulin regulation in a 9-year prospective study of 4,976 middle-aged participants in the French DESIR (Data from an Epidemiological Study on the Insulin Resistance Syndrome) cohort. Our data support previous studies associating the T at-risk allele with a higher prevalence of hyperglycemia at baseline (P ‫؍‬ 0.049) and a higher incidence of hyperglycemia after 9 years of follow-up (P ‫؍‬ 0.014). The population-attributable risk to develop hyperglycemia due to the T at-risk allele was estimated to be 10.4% at the end of the prospective study. The most likely inheritance model was found to be additive (P ‫؍‬ 0.002) rather than deviating from linearity (P ‫؍‬ 0.098). An increase in the incidence of hyperglycemia was confirmed by survival analyses among C/C, C/T, and T/T carriers during the 9 years of follow-up (P ‫؍‬ 0.028 by log-rank test). Interestingly, in control individuals, there was weak evidence of association of the T at-risk allele with reduced fasting insulin levels and insulin secretion index (homeostasis model assessment of ␤-cell function) in control individuals. We conclude that the TCF7L2 T at-risk allele variation (rs7903146) predicts hyperglycemia incidence in a general French population, possibly through a deleterious effect on insulin secretion. Diabetes 55: 3189 -3192, 2006

Association Study of the Genetic Polymorphisms of the Transcription Factor 7-Like 2 (TCF7L2) Gene and Type 2 Diabetes in the Chinese Population

“…Five single nucleotide polymorphisms (SNPs) (rs12255372, rs7903146, rs7901695, rs11196205, and rs7895340) within the LD block also showed similarly robust associations with type 2 diabetes (6). Further studies in other European populations, African Americans, Mexican Americans, and Asian Indians confirmed the strong associations with an estimated population attributable risk of 17-28% (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22). Several genome-wide association studies independently confirmed the strong associations of SNP rs7903146 in the TCF7L2 locus with type 2 diabetes (23)(24)(25)(26).…”

“…The polymorphism of TCF7L2 (rs7903146) is the strongest single genetic variant associated with type 2 diabetes (6,23-26) and has been convincingly replicated in multiple populations (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). In this study, we aimed to explore the effect of the TCF7L2 polymorphisms in a Han Chinese population.…”

The Effect of Three Months of Resistance Training on TCF7L2 Expression in Pancreas Tissues of Type 2 Diabetic Rats

“…This relationship is associated with defects in insulin production, and it is represented by reducing the release of insulin from pancreatic beta cells (37,38). Other studies have reported the association between rs7903146 T-allele with impaired glucose tolerance (34,38,39), increased birth weight (40), and increased anthropometric indices which show the role of the TCF7L2 phenotype in several tissues (33). It seems that the diabetic effect of TCF7L2 rs7903146 or TCF7L2-related variants is presented as reduced insulin secretion or defects in insulin function, reduced effect of glucagon-like peptide-1 (GLP-1), and increased hepatic glucose production (37,41,42).…”

“…Wegner et al (2008) have recently shown that the TCF7L2 rs7903146 T-allele is associated with impaired insulin secretion in elderly twins (43). It is known that each TCF7L2 rs7903146 T-allele increases the risk of type 2 diabetes, even in the presence of a weight loss of 1.37-fold (11,33,34,44). Several studies have also indicated that rs7903146 affects insulin production in type 2 diabetes through reducing the conversion of proinsulin to insulin.…”

“…Phenotypic changes in TCF7L2 indicate that type 2 diabetes exacerbates through or due to malfunctioning of beta cells (33)(34)(35). Changes in TCF7L2 expression and its variants are associated with impaired insulin secretion that reduces the capacity of insulin secretion in response to insulin sensitivity.…”