Haplotypes of Transcription Factor 7–Like 2 (TCF7L2) Gene and Its Upstream Region Are Associated With Type 2 Diabetes and Age of Onset in Mexican Americans

Abstract

1TCF7L2 acts as both a repressor and transactivator of genes, as directed by the Wnt signaling pathway. Recently, several highly correlated sequence variants located within a haplotype block of the TCF7L2 gene were observed to associate with type 2 diabetes in three Caucasian cohorts. We previously reported linkage of type 2 diabetes in the San Antonio Family Diabetes Study (SAFADS) cohort consisting of extended pedigrees of Mexican Americans to the region of chromosome 10q harboring TCF7L2. We therefore genotyped 11 single nucleotide polymorphisms (SNPs) from nine haplotype blocks across the gene in 545 SAFADS subjects (178 diabetic) to investigate their role in diabetes pathogenesis. We observed nominal association between four SNPs (rs10885390, rs7903146, rs12255372, and rs3814573) in three haplotype blocks and type 2 diabetes, age at diagnosis, and 2-h glucose levels (P ‫؍‬ 0.001-0.055). Furthermore, we identified a common protective haplotype defined by these four SNPs that was significantly associated with type 2 diabetes and age at diagnosis (P ‫؍‬ 4.2 ؋ 10 ؊5 , relative risk [RR] 0.69; P ‫؍‬ 6.7 ؋ 10 ؊6 , respectively) and a haplotype that confers diabetes risk that contains the rare alleles at SNPs rs10885390 and rs12255372 (P ‫؍‬ 0.02, RR 1.64). These data provide evidence that variation in the TCF7L2 genomic region may affect risk for type 2 diabetes in Mexican Americans, but the attributable risk may be lower than in Caucasian populations. Diabetes 56:389 -393, 2007 R ecently, a DNA sequence variant of the transcription factor 7-like 2 (TCF7L2, formerly TCF4) gene has been found to be significantly associated with type 2 diabetes in an Icelandic case-control study. This finding has been replicated in two other Caucasian case-control cohorts from Denmark and the U.S. (1). Interestingly, TCF7L2 has been shown to mediate regulation of glucagon-like peptide-1 expression (2), and this may be a mechanism by which alteration of this gene influences susceptibility to type 2 diabetes. The variant of TCF7L2 that has been observed to be associated with type 2 diabetes is a microsatellite marker (DG10S478) located in intron 3 (1). Additionally, the genotypes of five single nucleotide polymorphisms (SNPs) within the same large haplotype block that were correlated with DG10S478 were also associated with type 2 diabetes. The authors recommended that the two most highly correlated SNPs, rs12255372 and rs7903146, be included in replication attempts. Subsequently, these two SNPs have been associated with type 2 diabetes and impaired glucose tolerance in an Amish population and with measures of insulin sensitivity and insulin secretion in non-Amish, nondiabetic subjects (3). In addition, among participants of the Diabetes Prevention Program, TT homozygotes at these two SNPs were more likely to progress from impaired glucose tolerance to type 2 diabetes than noncarriers of the SNPs (4). We previously reported significant linkage of type 2 diabetes and its age of onset in the San Antonio Family Diabetes Study (SAFADS) co...

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).…”

Design of an allele-specific PCR assay to genotype the rs12255372 SNP in a pilot study of association between common TCF7L2 polymorphisms and type 2 diabetes in Venezuelans

“…Similarly, this polymorphism was found associated with diabetes in several works carried out in admixed populations from other Latin American countries (9,(23)(24)(25)28,29,31,32). However, Barros and cols.…”

“…Moreover, among Latin American countries there are only reports on the association of TCF7L2 polymorphisms and T2DM from Colombia (23), Brazil (24)(25)(26)(27)(28) and Mexico (9,(29)(30)(31)(32). Latin American populations are characterized by high socioeconomic and genetic heterogeneity with varying degrees of ancestral population proportions from country to country, thus more studies are needed exploring the basis of T2DM susceptibility from these mixed populations.…”

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).…”