Polymorphisms in the Transcription Factor 7-Like 2 (TCF7L2) Gene Are Associated With Type 2 Diabetes in the Amish

Abstract

Transcription factor 7-like 2 (TCF7L2) regulates genes involved in cell proliferation and differentiation. The TCF7L2 gene is located on chromosome 10q25 in a region of replicated linkage to type 2 diabetes. Recently, a microsatellite marker in intron 3 (DG10S478) and five correlated single nucleotide polymorphisms (SNPs) were identified in Icelandic individuals that showed strong association with type 2 diabetes, which was replicated in Danish and European-American cohorts. We genotyped four of the SNPs (rs7901695, rs7903146, rs11196205, and rs12255372) in Amish subjects with type 2 diabetes (n ‫؍‬ 137), impaired glucose tolerance (IGT; n ‫؍‬ 139), and normal glucose tolerance (NGT; n ‫؍‬ 342). We compared genotype frequencies in subjects with type 2 diabetes with those with NGT and found marginal association for rs7901695 (P ‫؍‬ 0.05; odds ratio [OR] 1.51); comparison between NGT control subjects and the combined type 2 diabetes/IGT case group showed strong association with rs7901695 and rs7903146 (P ‫؍‬ 0.008 -0.01; OR 1.53-1.57) and marginal association with rs11196205 and rs12255372 (P ‫؍‬ 0.07 and P ‫؍‬ 0.04, respectively). In an expanded set of 698 Amish subjects without diabetes, we found no association with insulin and glucose levels during a 3-h oral glucose tolerance test. We also genotyped these SNPs in nondiabetic, non-Amish subjects (n ‫؍‬ 48), in whom intravenous glucose tolerance tests were performed, and found an association between rs7901695 and rs7903146 and insulin sensitivity (P ‫؍‬ 0.003 and P ‫؍‬ 0.005, respectively) and disposition index (P ‫؍‬ 0.04 and P ‫؍‬ 0.007, respectively). These data provide replicating evidence that variants in TCF7L2 increase the risk for type 2 diabetes and novel evidence that the variants likely influence both insulin secretion and insulin sensitivity. Diabetes 55:2654 -2659, 2006 T he transcription factor 7-like 2 (TCF7L2) gene is a member of the T-cell factor (TCF)/lymphoidenhancing factor family of high mobility group box-containing transcription factors involved in the Wnt signaling pathway. This pathway is a key component to the regulation of cell proliferation and differentiation. Wnt signaling is initiated by the binding of Wnts to their receptor complex, which results in the release of ␤-catenin from its degradation complex and translocation to the nucleus. In the nucleus, ␤-catenin heterodimerizes with the TCF/lymphoid-enhancing factor family of transcription factors to regulate the expression of Wnt target genes (1,2).The TCF7L2 gene spans 215.9 kb on chromosome 10q25, a region of replicated linkage to type 2 diabetes in Mexican-American (3) and Icelandic (4) cohorts. Recently, Grant et al. (5) identified a microsatellite marker (DG10S478) in intron 3 of TCF7L2 that showed strong association with type 2 diabetes in Icelandic, Danish, and European-American populations. The authors then genotyped the five single nucleotide polymorphisms (SNPs) from the CEPH Utah (CEU) HapMap samples with the strongest correlation to DG10S478 (rs12255372, rs7903146, rs7...

A genetic variation of the transcription factor 7-like 2 gene is associated with risk of type 2 diabetes in the Japanese population

“…In this study, we found a significant association in samples from a Japanese population between the variation in TCF7L2 and type 2 diabetes, an association similar to that previously reported in samples from European and European-origin populations [4,[7][8][9][10][11][12][13]. It is noteworthy that the association between the SNP in TCF7L2 and type 2 diabetes has consistently been observed in different ethnic groups [14,15], which supports the reliability of both previous studies as well as our present study.…”

Variants of the TCF7L2 gene are associated with beta cell dysfunction and confer an increased risk of type 2 diabetes mellitus in the ULSAM cohort of Swedish elderly men

“…While our study was in progress, the risk alleles of the two SNPs were shown to be associated with decreased levels of insulin in plasma and to affect progression to diabetes in subjects with impaired glucose tolerance [10]. Based on these findings, it has been suggested that the increased risk of type 2 diabetes mellitus associated with TCF7L2 could be caused by impaired beta cell function affecting glucose-stimulated insulin secretion [7,10,11,18].…”

“…Grant et al suggested that two SNPs (rs12255372 and rs7903146) [3] be analysed for replication of their finding in other populations. Since the original publication, a number of studies have confirmed the association between TCF7L2 and type 2 diabetes mellitus in European, Asian and American cohorts [4][5][6][7][8][9][10][11][12][13][14][15].…”

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).…”