Refining the impact of TCF7L2 gene variants on type 2 diabetes and adaptive evolution

Abstract

We recently described an association between risk of type 2diabetes and variants in the transcription factor 7-like 2 gene (TCF7L2; formerly TCF4), with a population attributable risk (PAR) of 17%-28% in three populations of European ancestry. Here, we refine the definition of the TCF7L2 type 2diabetes risk variant, HapB(T2D), to the ancestral T allele of a SNP, rs7903146, through replication in West African and Danish type 2 diabetes case-control studies and an expanded Icelandic study. We also identify another variant of the same gene, HapA, that shows evidence of positive selection in East Asian, European and West African populations. Notably, HapA shows a suggestive association with body mass index and altered concentrations of the hunger-satiety hormones ghrelin and leptin in males, indicating that the selective advantage of HapA may have been mediated through effects on energy metabolism.

Testing the association of novel meta-analysis-derived diabetes risk genes with type II diabetes and related metabolic traits in Asian Indian Sikhs

“…35) and has been replicated in subsequent studies in many different ethnicities. [8][9][10][11][12][13][14][15][16] The association of other newly emerged GWAS loci, such as IGF2BP2, CDKAL1, CDKN2A/B, HHEX, SLC30A8 and KCNJ11, was replicated in Japanese; 17,18 IGF2BP2, SLC30A8, HHEX, CDKAL1, CDKN2A/B and FTO in Asians from Hong Kong and Korea; 19 IGF2BP2, CDKAL1, CDKN2A/B, HHEX and SLC30A8 in Han Chinese; 20 and IGF2BP2, PPARG2 and FTO in Indian Sikhs. 21 More recently, a meta-analysis of three large GWA studies by the Diabetes Genetics Replication and Meta-analysis (DIAGRAM) Consortium identified six additional T2D loci (NOTCH2, THADA, ADAMTS9, JAZF1, CDC123/CAMKID and TSPAN8/LGRS) to be strongly associated with increased susceptibility to T2D with modest ORs (1.15À1.3).…”

The T allele of rs7903146 TCF7L2 is associated with impaired insulinotropic action of incretin hormones, reduced 24 h profiles of plasma insulin and glucagon, and increased hepatic glucose production in young healthy men

“…Several studies have reported a link between variants in the TCF7L2 gene and type 2 diabetes [1][2][3][4][5][6][7][8] and in a recent meta-analysis, rs7903146 of TCF7L2 was associated with type 2 diabetes with allelic odds ratios of 1.46, making it the single strongest known genetic risk factor for type 2 diabetes [9].…”

Redundant enhancers and causal variants in the TCF7L2 gene

“…[8][9][10] The present letter discussed published data from European and nonEuropean populations and postulated that an independent secondary signal tagged by the rs12255372 SNP is also present in the TCF7L2 gene. The author also discussed recent results that show the presence of multiple enhancers in the TCF7L2 gene, 6,7 and advanced the hypothesis that these enhancers are redundant and there is person-to-person variability in their use.…”

“…[8][9][10] However, a critical assessment of published results does not rule out the presence of an independent secondary signal. Helgason et al 8 carried out haplotype analysis of SNPs, rs7903146 and rs12255372, and the microsatellite DG10S478 (ie, the three markers that were initially found with the strongest association with T2D 11 ) in Danish and Icelandic populations, and concluded that rs7903146 is the most likely causal variant.…”