The TCF7L2 gene is the locus with the strongest association with risk of type 2 diabetes (T2D) in different populations.1, 2 The rs7903146 single-nucleotide polymorphism (SNP), located in intron 3 and the one with the strongest association to T2D risk, has been the most widely studied TCF7L2 variant. Current evidence suggests that rs7903146 may affect risk of T2D through its effects on enhancer activity3, 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 More recently Savic et al6, 7 reported that the TCF7L2 gene harbors several highly conserved cis-regulatory elements that show both in vitro and in vivo enhancer activity. These enhancer elements are located in a 92-kb interval that harbors all the TCF7L2 SNPs, not just rs7903146, associated with T2D risk. The physical overlap between multiple enhancer elements and TCF7L2 variants suggests that this gene may carry more than one causal variant related to the development of T2D. The present letter discusses the implications of these recent findings and presents possible mechanisms in how genetic variants in the TCF7L2 gene may affect the development of T2D.
