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

  1. Richa Saxena123,
  2. Lauren Gianniny1,
  3. Noël P. Burtt1,
  4. Valeriya Lyssenko4,
  5. Candace Giuducci1,
  6. Marketa Sjögren4,
  7. Jose C. Florez125,
  8. Peter Almgren4,
  9. Bo Isomaa6,
  10. Marju Orho-Melander4,
  11. Ulf Lindblad47,
  12. Mark J. Daly125,
  13. Tiinamaija Tuomi6,
  14. Joel N. Hirschhorn158,
  15. Kristin G. Ardlie19,
  16. Leif C. Groop46 and
  17. David Altshuler1235
  1. 1Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts
  2. 2Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts
  3. 3Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts
  4. 4Department of Clinical Sciences, Diabetes and Endocrinology, University Hospital Malmö, Lund University, Malmö, Sweden
  5. 5Department of Medicine, Harvard Medical School, Boston, Massachusetts
  6. 6Department of Medicine, Helsinki University Central Hospital, Folkhalsan Genetic Institute, Folkhalsan Research Center and Research Program for Molecular Medicine, University of Helsinki, Helsinki, Finland
  7. 7Skaraborg Institute, Skövde, Sweden
  8. 8Divisions of Genetics and Endocrinology, Children’s Hospital, Boston, Massachusetts
  9. 9Genomics Collaborative, Cambridge, Massachusetts
  1. 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}


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.


  • L.C.G. has served on advisory boards for and received consulting fees from sanofi-aventis, Bristol-Myers Squibb, GlaxoSmithKline, Kowa, and Roche.

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    • Accepted June 27, 2006.
    • Received March 22, 2006.
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