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 ,
Noël P. Burtt 1 ,
Valeriya Lyssenko 4 ,
Candace Giuducci 1 ,
Marketa Sjögren 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
1 Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge,
Massachusetts
2 Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts
3 Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts
4 Department of Clinical Sciences, Diabetes and Endocrinology, University Hospital Malmö, Lund University, Malmö, Sweden
5 Department of Medicine, Harvard Medical School, Boston, Massachusetts
6 Department of Medicine, Helsinki University Central Hospital, Folkhalsan Genetic Institute, Folkhalsan Research Center and
Research Program for Molecular Medicine, University of Helsinki, Helsinki, Finland
7 Skaraborg Institute, Skövde, Sweden
8 Divisions of Genetics and Endocrinology, Children’s Hospital, Boston, Massachusetts
9 Genomics Collaborative, Cambridge, Massachusetts
Address correspondence and reprint requests to David Altshuler, Department of Molecular Biology/Endocrinology and Massachusetts
General Hospital, Simches Research Building, 175 Cambridge St., CPZN-6818, Boston, MA 02114. E-mail: altshuler{at}molbio.mgh.harvard.edu
Abstract
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 associated 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.
AUC, area under the curve
IGT, impaired glucose tolerance
NGT, normal glucose tolerance
OGTT, oral glucose tolerance test
SNP, single nucleotide polymorphism
Footnotes
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 .
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted June 27, 2006.
Received March 22, 2006.
DIABETES

Diabetes (New York, N.Y.), 2006-10, Vol.55 (10), p.2890-2895

Common Single Nucleotide Polymorphisms in TCF7L2 Are Reproducibly Associated With Type 2 Diabetes and Reduce the Insulin Response to Glucose in Nondiabetic Individuals