Common Variants in Maturity-Onset Diabetes of the Young Genes Contribute to Risk of Type 2 Diabetes in Finns

  1. Lori L. Bonnycastle1,
  2. Cristen J. Willer2,
  3. Karen N. Conneely2,
  4. Anne U. Jackson2,
  5. Cecily P. Burrill1,
  6. Richard M. Watanabe3,
  7. Peter S. Chines1,
  8. Narisu Narisu1,
  9. Laura J. Scott2,
  10. Sareena T. Enloe1,
  11. Amy J. Swift1,
  12. William L. Duren2,
  13. Heather M. Stringham2,
  14. Michael R. Erdos1,
  15. Nancy L. Riebow1,
  16. Thomas A. Buchanan4,
  17. Timo T. Valle5,
  18. Jaakko Tuomilehto567,
  19. Richard N. Bergman8,
  20. Karen L. Mohlke9,
  21. Michael Boehnke2 and
  22. Francis S. Collins1
  1. 1Genome Technology Branch, National Genome Research Institute, Bethesda, Maryland
  2. 2Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, Michigan
  3. 3Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California
  4. 4Department of Medicine, Division of Endocrinology, Keck School of Medicine, University of Southern California, Los Angeles, California
  5. 5Diabetes and Genetic Epidemiology Unit, Department of Epidemiology and Health Promotion, National Public Health Institute, Helsinki, Finland
  6. 6Department of Public Health, University of Helsinki, Helsinki, Finland
  7. 7South Ostrobothnia Central Hospital, Seinäjoki, Finland
  8. 8Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California
  9. 9Department of Genetics, University of North Carolina, Chapel Hill, North Carolina
  1. Address correspondence and reprint requests to Francis S. Collins, MD, PhD, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892-2152. E-mail: francisc{at}mail.nih.gov

Abstract

Prior reports have suggested that variants in the genes for maturity-onset diabetes of the young (MODY) may confer susceptibility to type 2 diabetes, but results have been conflicting and coverage of the MODY genes has been incomplete. To complement our previous studies of HNF4A, we examined the other five known MODY genes for association with type 2 diabetes in Finnish individuals. For each of the five genes, we selected 1) nonredundant single nucleotide polymorphisms (SNPs) (r2< 0.8 with other SNPs) from the HapMap database or another linkage disequilibrium map, 2) SNPs with previously reported type 2 diabetes association, and 3) nonsynonymous coding SNPs. We tested 128 SNPs for association with type 2 diabetes in 786 index cases from type 2 diabetic families and 619 normal glucose-tolerant control subjects. We followed up 35 of the most significant SNPs by genotyping them on another 384 case subjects and 366 control subjects from Finland. We also supplemented our previous HNF4A results by genotyping 12 SNPs on additional Finnish samples. After correcting for testing multiple correlated SNPs within a gene, we find evidence of type 2 diabetes association with SNPs in five of the six known MODY genes: GCK, HNF1A, HNF1B, NEUROD1, and HNF4A. Our data suggest that common variants in several MODY genes play a modest role in type 2 diabetes susceptibility.

Footnotes

  • L.L.B. and C.J.W. contributed equally to this work.

    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 15, 2006.
    • Received February 7, 2006.
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  1. doi: 10.2337/db06-0178 Diabetes September 2006 vol. 55 no. 9 2534-2540
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