Mechanisms by which common variants in the TCF7L2 gene increase risk of type 2 diabetes

Abstract

Genetic variants in the gene encoding for transcription factor-7-like 2 (TCF7L2) have been associated with type 2 diabetes (T2D) and impaired β cell function, but the mechanisms have remained unknown. We therefore studied prospectively the ability of common variants in TCF7L2 to predict future T2D and explored the mechanisms by which they would do this. Scandinavian subjects followed for up to 22 years were genotyped for 3 SNPs (rs7903146, rs12255372, and rs10885406) in TCF7L2, and a subset of them underwent extensive metabolic studies. Expression of TCF7L2 was related to genotype and metabolic parameters in human islets. The CT/TT genotypes of SNP rs7903146 strongly predicted future T2D in 2 independent cohorts (Swedish and Finnish). The risk T allele was associated with impaired insulin secretion, incretin effects, and enhanced rate of hepatic glucose production. TCF7L2 expression in human islets was increased 5-fold in T2D, particularly in carriers of the TT genotype. Overexpression of TCF7L2 in human islets reduced glucose-stimulated insulin secretion. In conclusion, the increased risk of T2D conferred by variants in TCF7L2 involves the enteroinsular axis, enhanced expression of the gene in islets, and impaired insulin secretion.

Beta cell glucose sensitivity is decreased by 39% in non-diabetic individuals carrying multiple diabetes-risk alleles compared with those with no risk alleles

“…First, we confirmed that the TCF7L2 risk allele was individually associated with decreased early insulin response to an OGTT (p=0.038) as previously reported [15]. Combining the diabetes-risk alleles for CDKAL1 (rs10946398), HHEX/IDE (rs1111875) and TCF7L2 (rs7903146) loci showed an additive model of association with measures of beta cell function.…”

“…We also included TCF7L2 (rs7903146), as it remains the strongest genetic predictor of type 2 diabetes, and has been reported to associate with decreased pancreatic beta cell function [8,15]. We next included these loci and those of the other four genes reported to alter beta cell function, CDKN2A/B (rs10811661), IGF2BP2 (rs4402960), SLC30A8 (rs13266634) and KCNJ11 (rs5219), in our model to test the effects of all seven variants.…”

Wnt4 antagonises Wnt3a mediated increases in growth and glucose stimulated insulin secretion in the pancreatic beta-cell line, INS-1

“…Subsequent studies implicated β-cell dysfunction as the underlying cause of diabetes in patients with the TCF7L2 risk variant [2][3][4][5] and have suggested that Wnt signalling plays an important role in both pancreatic development and in the function of mature pancreatic islets [6]. The activation of the canonical Wnt pathway, by ligands such as Wnt3a, has been of particular interest as it can increase β-cell proliferation, decrease apoptosis and improve glucose stimulated insulin secretion [6][7][8][9][10][11][12].…”

Redundant enhancers and causal variants in the TCF7L2 gene

“…Current evidence suggests that rs7903146 may affect risk of T2D through its effects on enhancer activity 3,4 resulting in higher TCF7L2 gene expression. [3][4][5] The rs7903146 SNP has been found located inside islet-selective open chromatin sites using either formaldehyde-assisted isolation of regulatory elements coupled with high throughput sequencing (FAIRE-seq), 3 or histone H3 lysine methylation modifications as marks of regulatory elements. 4 In addition, the T-allele of rs7903146 (ie, the allele associated with higher risk of T2D) has been found associated with higher TCF7L2 gene expression in human pancreatic islets, 5 and in luciferase reporter assays in the mouse pancreatic MIN6 cell line, 3,4 and the rat pancreatic 832/13 cell line.…”

“…[3][4][5] The rs7903146 SNP has been found located inside islet-selective open chromatin sites using either formaldehyde-assisted isolation of regulatory elements coupled with high throughput sequencing (FAIRE-seq), 3 or histone H3 lysine methylation modifications as marks of regulatory elements. 4 In addition, the T-allele of rs7903146 (ie, the allele associated with higher risk of T2D) has been found associated with higher TCF7L2 gene expression in human pancreatic islets, 5 and in luciferase reporter assays in the mouse pancreatic MIN6 cell line, 3,4 and the rat pancreatic 832/13 cell line. 3 More recently Savic et al 6,7 reported that the TCF7L2 gene harbors several highly conserved cis-regulatory elements that show both in vitro and in vivo enhancer activity.…”