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DOI: 10.2337/db06-0338
© 2006 by the American Diabetes Association
Brief Genetics Reports |
Polymorphisms in the Transcription Factor 7-Like 2 (TCF7L2) Gene Are Associated With Type 2 Diabetes in the Amish
Replication and Evidence for a Role in Both Insulin Secretion and Insulin Resistance
1 Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, Maryland
2 Geriatric Research and Education Clinical Center, Veterans Administration Medical Center, Baltimore, Maryland
Address correspondence and reprint requests to Coleen M. Damcott, PhD, Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, 660 West Redwood St., Rm. 592, Baltimore, MD 21201. E-mail: cdamcott{at}medicine.umaryland.edu
Abbreviations:
AFDS, Amish Family Diabetes Study; AIRg, acute insulin response to glucose; DI, disposition index; IGT, impaired glucose tolerance; IVGTT, intravenous glucose tolerance test; LD, linkage disequilibrium; NGT, normal glucose tolerance; OGTT, oral glucose tolerance test; SNP, single nucleotide polymorphism; TCF, T-cell factor
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.
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