G-allele of Intronic rs10830963 in MTNR1B Confers Increased Risk of Impaired Fasting Glycemia and Type 2 Diabetes Through an Impaired Glucose-Stimulated Insulin Release

Studies Involving 19,605 Europeans

  1. Thomas Sparsø1,
  2. Amélie Bonnefond2,
  3. Ehm Andersson1,
  4. Nabila Bouatia-Naji2,
  5. Johan Holmkvist1,
  6. Lise Wegner1,
  7. Niels Grarup1,
  8. Anette P. Gjesing1,
  9. Karina Banasik1,
  10. Christine Cavalcanti-Proença2,
  11. Marion Marchand2,
  12. Martine Vaxillaire2,
  13. Guillaume Charpentier3,
  14. Marjo-Riitta Jarvelin4,
  15. Jean Tichet5,
  16. Beverley Balkau6,
  17. Michel Marre7,
  18. Claire Lévy-Marchal8,
  19. Kristine Færch1,
  20. Knut Borch-Johnsen1,9,
  21. Torben Jørgensen1011,
  22. Sten Madsbad1112,
  23. Pernille Poulsen1,
  24. Allan Vaag1,
  25. Christian Dina2,
  26. Torben Hansen1,13,
  27. Oluf Pedersen1,9,11 and
  28. Philippe Froguel2,14
  1. 1Steno Diabetes Center, Gentofte, Denmark;
  2. 2CNRS-UMR-8090, Institute of Biology and Lille 2 University, Pasteur Institute, Lille, France;
  3. 3Endocrinology-Diabetology Unit, Corbeil-Essonnes Hospital, Essonnes, France;
  4. 4Department of Epidemiology and Public Health, Imperial College London, London, U.K., and Institute of Health Sciences, University of Oulu, Finland, Department of Child and Adolescent Health, National Public Health Institute, Finland, Biocenter Oulu, University of Oulu, Oulu, Finland;
  5. 5Institut Inter-Régional pour la Santé (IRSA), La Riche, France;
  6. 6INSERM U780, Villejuif, and University Paris-Sud, Orsay, France;
  7. 7Department of Endocrinology, Diabetology and Nutrition, Bichat-Claude Bernard University Hospital, Assistance Publique des Hôpitaux de Paris, Paris, France, and INSERM U695, Université Paris 7, Paris, France;
  8. 8INSERM, Unité 690, Robert Debré Hospital, Paris, France, and Paris Diderot University, Paris, France;
  9. 9Faculty of Health Sciences, University of Aarhus, Aarhus, Denmark;
  10. 10Research Centre for Prevention and Health, Glostrup University Hospital, Glostrup, Denmark;
  11. 11Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark;
  12. 12Hvidovre University Hospital, Hvidovre, Denmark;
  13. 13Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark;
  14. 14Genomic Medicine, Hammersmith Hospital, Imperial College London, U.K.
  1. Corresponding author: Thomas Sparsø, tspr{at}steno.dk.
  1. T.S. and A.B. contributed equally to this work.

Abstract

OBJECTIVE Genome-wide association studies have identified several variants within the MTNR1B locus that are associated with fasting plasma glucose (FPG) and type 2 diabetes. We refined the association signal by direct genotyping and examined for associations of the variant displaying the most independent effect on FPG with isolated impaired fasting glycemia (i-IFG), isolated impaired glucose tolerance (i-IGT), type 2 diabetes, and measures of insulin release and peripheral and hepatic insulin sensitivity.

RESEARCH DESIGN AND METHODS We examined European-descent participants in the Inter99 study (n = 5,553), in a sample of young healthy Danes (n = 372), in Danish twins (n = 77 elderly and n = 97 young), in additional Danish type 2 diabetic patients (n = 1,626) and control subjects (n = 505), in the Data from the Epidemiological Study on the Insulin Resistance Syndrome (DESIR) study (n = 4,656), in the North Finland Birth Cohort 86 (n = 5,258), and in the Haguenau study (n = 1,461).

RESULTS The MTNR1B intronic variant, rs10830963, carried most of the effect on FPG and showed the strongest association with FPG (combined P = 5.3 × 10−31) and type 2 diabetes. The rs10830963 G-allele increased the risk of i-IFG (odds ratio [OR] 1.64, P = 5.5 × 10−11) but not i-IGT. The G-allele was associated with a decreased insulin release after oral and intravenous glucose challenges (P < 0.01) but not after injection of tolbutamide. In elderly twins, the G-allele associated with hepatic insulin resistance (P = 0.017).

CONCLUSIONS The G-allele of MTNR1B rs10830963 increases risk of type 2 diabetes through a state of i-IFG and not through i-IGT. The same allele associates with estimates of β-cell dysfunction and hepatic insulin resistance.

Footnotes

  • 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.

    • Received December 1, 2008.
    • Accepted March 12, 2009.
  • Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

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