Brief Genetics Report Common Single Nucleotide Polymorphisms in TCF7L2 Are Reproducibly Associated With Type 2 Diabetes and Reduce the Insulin Response to Glucose in Nondiabetic Individuals Richa Saxena, 1,2,3 Lauren Gianniny, 1 Noe ¨l P. Burtt, 1 Valeriya Lyssenko, 4 Candace Giuducci, 1 Marketa Sjo ¨ gren, 4 Jose C. Florez, 1,2,5 Peter Almgren, 4 Bo Isomaa, 6 Marju Orho-Melander, 4 Ulf Lindblad, 4,7 Mark J. Daly, 1,2,5 Tiinamaija Tuomi, 6 Joel N. Hirschhorn, 1,5,8 Kristin G. Ardlie, 1,9 Leif C. Groop, 4,6 and David Altshuler 1,2,3,5 Recently, common noncoding variants in the TCF7L2 gene were strongly associated with increased risk of type 2 diabetes in samples from Iceland, Denmark, and the U.S. We genotyped 13 single nucleotide polymorphisms (SNPs) across TCF7L2 in 8,310 individuals in family-based and case-control designs from Scandinavia, Poland, and the U.S. We convincingly confirmed the previous association of TCF7L2 SNPs with the risk of type 2 diabetes (rs7903146T odds ratio 1.40 [95% CI 1.30 –1.50], P  6.74  10 20 ). In nondiabetic individuals, the risk genotypes were associ- ated with a substantial reduction in the insulinogenic index derived from an oral glucose tolerance test (risk allele homozygotes have half the insulin response to glucose of noncarriers, P  0.003) but not with increased insulin resistance. These results suggest that TCF7L2 variants may act through insulin secretion to increase the risk of type 2 diabetes. Diabetes 55:2890 –2895, 2006 T ype 2 diabetes is highly heritable, but known variants explain only a small fraction of the overall genetic risk in the population. Recently, Grant et al. (1) reported a strong association of variants in TCF7L2 with increased risk of type 2 diabetes in an Icelandic sample, and this association was confirmed in Caucasian samples from Denmark and the U.S. (com- bined odds ratio [OR] 1.56, P = 4.7  10 -18 ). Testing of this association in other well-phenotyped samples is needed to 1) validate the association, 2) estimate the true effect size, and 3) identify effects on intermediate traits that may suggest how TCF7L2 variants act (e.g., through changes in insulin secretion, insulin resistance, BMI, waist-to-hip ratio). TCF7L2 has been implicated as a member of the Wnt signaling pathway and was previously well studied only in colon cancer. However, based on its role in intestinal cells (2), Grant et al. (1) proposed that variants of TCF7L2 may alter levels of glucagon-like peptide 1, which influences insulin secretion from the -cells of the pancreas. Thus, one hypothesis is that TCF7L2 might influence the risk of type 2 diabetes by influencing insulin secretion. Alterna- tively, a gene increasing the risk of diabetes could act through insulin action or through currently unknown mechanisms. To evaluate these questions, we selected tag SNPs to capture common variation in a 64.6-kb region of strong linkage disequilibrium surrounding the most significant association signal and spanning intron 3, exon 4, and intron 4 of TCF7L2. We genotyped 13 tag SNPs that capture 32 of 44 variants with r 2  0.8 (mean r 2  0.985) in the phase II HapMap CEU population (3); all 5 SNPs that were most highly correlated with the DG10S478 allele X in the original report (1) were directly genotyped. The tag SNPs were genotyped in well-characterized family-based and case-control samples from Scandinavia, Poland, and the U.S.; phenotypic characteristics of all samples are described in Table 1. We included five previ- ously described patient samples that have formed the basis of multiple previous publications from our research group: 333 Swedish and Finnish trios; 2 Scandinavian case-control samples with 918 and 1,010 subjects, respec- From the 1 Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachu- setts; the 2 Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts; the 3 Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts; the 4 Department of Clinical Sciences, Diabetes and Endocrinology, University Hospital Malmo ¨, Lund University, Malmo ¨ , Sweden; the 5 Department of Medicine, Harvard Medical School, Boston, Massachusetts; the 6 Department of Medicine, Hel- sinki University Central Hospital, Folkhalsan Genetic Institute, Folkhalsan Research Center and Research Program for Molecular Medicine, University of Helsinki, Helsinki, Finland; the 7 Skaraborg Institute, Sko ¨ vde, Sweden; the 8 Divisions of Genetics and Endocrinology, Children’s Hospital, Boston, Mas- sachusetts; and 9 Genomics Collaborative, Cambridge, Massachusetts. Address correspondence and reprint requests to David Altshuler, Depart- ment of Molecular Biology/Endocrinology and Massachusetts General Hospi- tal, Simches Research Building, 175 Cambridge St., CPZN-6818, Boston, MA 02114. E-mail: altshuler@molbio.mgh.harvard.edu. Received for publication 22 March 2006 and accepted in revised form 27 June 2006. L.C.G. has served on advisory boards for and received consulting fees from sanofi-aventis, Bristol-Myers Squibb, GlaxoSmithKline, Kowa, and Roche. Additional information for this article can be found in an online appendix at http://diabetes.diabetesjournals.org. AUC, area under the curve; IGT, impaired glucose tolerance; NGT, normal glucose tolerance; OGTT, oral glucose tolerance test; SNP, single nucleotide polymorphism. DOI: 10.2337/db06-0381 © 2006 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. 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