TCF7L2 Is Not a Major Susceptibility Gene for Type 2 Diabetes in Pima Indians

Abstract

OBJECTIVE-The transcription factor 7-like 2 (TCF7L2) gene was initially reported to be associated with type 2 diabetes in Icelandic, Danish, and U.S. populations. We investigated whether TCF7L2 also has a role in type 2 diabetes susceptibility in Pima Indians. RESEARCH DESIGN AND METHODS-The six variants reported to be associated with type 2 diabetes in the Icelandic study were genotyped in a population-based sample of 3,501 Pima Indians (1,561 subjects had type 2 diabetes, and 1,940 did not have diabetes). In addition, the coding and promoter regions of TCF7L2 were sequenced in 24 Pima subjects. The one variant identified by sequencing, 35 additional database variants positioned in introns, and the six variants reported in the Icelandic study were genotyped in Pima families to determine the haplotype structure of TCF7L2 among Pima Indians. Fourteen representative variants were selected and genotyped in 3,501 Pima Indians. RESULTS-The six variants initially reported to be associated with type 2 diabetes were less common in Pima Indians compared with samples of European origin, and none were associated with type 2 diabetes. One representative variant, rs1225404, was nominally associated with type 2 diabetes in a general model (additive P ϭ 0.03, dominant P ϭ 0.005) but not in a within-family analysis (additive P ϭ 0.2, dominant P ϭ 0.07). However, several variants were associated with BMI; in particular, rs12255372 was associated in both general and within-family analyses (both P ϭ 0.0007). Modest associations were also found with traits predictive for type 2 diabetes. A microsatellite marker (DG10S478) within intron 3 of the transcription factor 7-like 2 (TCF7L2) gene and five intronic single nucleotide polymorphisms (SNPs) have been reported to be highly associated with type 2 diabetes in subjects from Iceland, Denmark, and the U.S. (1). Associations with these specific variants and type 2 diabetes have subsequently been replicated consistently and robustly in multiple studies involving subjects of European origin (2-11), Asian Indians (12), and Japanese subjects (13,14). To investigate whether variation in TCF7L2 also has a major role in type 2 diabetes susceptibility in Pima Indians, a population with an extraordinarily high prevalence of type 2 diabetes, variants from the initial report (1), as well as 14 additional representative variants, were genotyped in a population-based sample of full-heritage Pima Indians for association analyses. CONCLUSIONS-Variation RESEARCH DESIGN AND METHODSAll subjects are Pima Indians who are participants in our ongoing longitudinal study of type 2 diabetes among members of the Gila River Indian Community (15). Initially, a family-based sample was genotyped to determine the haplotype structure in this population, and representative SNPs were subsequently genotyped in a population-based sample for association analyses. The familybased sample consisted of 1,037 subjects (578 with type 2 diabetes and 459 without diabetes) from 332 nuclear families in 112 pedigrees. The population...

Association of TCF7L2 Gene Polymorphisms with T2DM in the Population of Juana Koslay, San Luis Province, Argentina

“…Thus our results reiterate TCF7L2 as the most promising T2DM susceptible gene that has been most universally replicated. While the risk allele of each of the two TCF7L2 SNPs was highly significantly associated with T2DM, the greatest risk of developing the disease was conferred by rs7903146, which is consistent with the findings from other studies, such as white Europeans, West Africans, Mexicans, African Americans, Indians, and Japanese [6] [33] [34], with the exception of the study on Pima Indian populations, in which contradictory results have been reported [31].…”

“…Among the TCF7L2 SNPs investigated, four are well-studied, and included rs7903146, rs7901695, rs12255372, rs11196205; of which rs7903146 and rs12255372 are the most investigated [6] [17] [31]. These variants are in strong linkage disequilibrium (LD), which allowed the identification of specific TCF7L2 haplotypes based on LD pattern [6] [17] [32].…”

The TCF7L2 rs7903146 (C/T) polymorphism is associated with risk to type 2 diabetes mellitus in Southern-Brazil

“…Here, we successfully replicated the association between the TCF7L2 rs7903146 SNP and risk for T2DM in Caucasian-Brazilian subjects from Southern of Brazil, probably under an additive inheritance model given that the risk conferred by the T/T genotype was higher than that conferred by heterozygous genotype. The consistency in the data showing the association between TCF7L2 gene variants and risk for T2DM reported by many studies in different populations is believed to be a reliable indicative of a universal contribution of this gene to T2DM development (31), even though some studies have reported weak or no association with the disease, mainly in Asian populations (21,(32)(33)(34)(35). Thus, to date, around 10 meta-analyses evaluated the pooled effect of TCF7L2 rs7903146 SNP in T2DM risk (5)(6)(7)(8)31,(36)(37)(38)(39)(40).…”

Racial differences in the interaction between family history and risk factors associated with diabetes in the National Health and Nutritional Examination Survey, 1999–2004

“…Of note, the few studies in African American, Hispanic, or Pima Indian populations that have tried to replicate previously identified diabetes risk alleles discovered in genome-wide association studies have failed to replicate many of these associations. 11,13,14,46 Formal tests of genotype by obesity interaction or stratified association analysis based on obesity status would help to clarify this.…”

“…Interestingly, although the initial discoveries have been made primarily in white populations, the few published studies that have attempted to replicate these associations in non-white populations have in large part failed to do so. [11][12][13][14] Nonetheless, full consideration has not been given to the possible modifying effect of important diabetes covariates on genetic risk factors, and whether ethnic differences in the distribution or effect of these risk factors would improve our ability to find genes underlying diabetes or enhance their generalizability or clinical utility once found.…”