The 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 Sparsø, MSc (tspr{at}steno.dk)1,
  2. Amélie Bonnefond, MSc2,
  3. Ehm Andersson, MSc1,
  4. Nabila Bouatia-Naji, PhD2,
  5. Johan Holmkvist, PhD1,
  6. Lise Wegner, MSc1,
  7. Niels Grarup, MD1,
  8. Anette P. Gjesing, MSC1,
  9. Karina Banasik, MSc1,
  10. Christine Cavalcanti-Proença, MSc1,
  11. Marion Marchand, MSc2,
  12. Martine Vaxillaire, PhD2,
  13. Guillaume Charpentier, MD3,
  14. Marjo-Riitta Jarvelin4,
  15. Jean Tichet5,
  16. Beverley Balkau6,
  17. Michel Marre, MD7,
  18. Claire Lévy-Marcha, MD8,
  19. Kristine Faerch, MSc1,
  20. Knut Borch-Johnsen, MD, DMSc1,9,
  21. Torben Jørgensen, DMSc10,11,
  22. Sten Madsbad, MD, DMSc11,12,
  23. Pernille Poulsen, MD, PhD1,
  24. Allan Vaag, MD, DMSc1,
  25. Christian Dina, MD2,
  26. Torben Hansen, MD, PhD1,13,
  27. Oluf Pedersen, MD, DMSc1,9,11 and
  28. Philippe Froguel, MD, PhD2,14
  1. 1Steno Diabetes Center, Gentofte, Denmark
  2. 2CNRS-UMR-8090, Institute of Biology and Lille 2 University, Pasteur Institute, F-59019 Lille, France
  3. 3Endocrinology-Diabetology Unit, Corbeil-Essonnes Hospital, Essonnes, F-91108 France
  4. 4Department of Epidemiology and Public Health, Imperial College London, W2 1PG London, UK 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, FIN-90014 Oulu, Finland
  5. 5Institut inter-régional pour la santé (IRSA), F-37521 La Riche, France
  6. 6INSERM U780, Villejuif, F-94807 and University Paris-Sud, Orsay, F-91405, France
  7. 7Department of Endocrinology, Diabetology and Nutrition, Bichat-Claude Bernard University Hospital, Assistance Publique des Hôpitaux de Paris, F-75018 Paris, France, and INSERM U695, Université Paris 7, F-75870 Paris, France
  8. 8INSERM, Unité 690, Robert Debré hospital, Paris, F-75019, France, Paris Diderot University, Paris, F-75005, 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, UK

    Abstract

    Objective. Genome wide association studies have identified several variants within the MTNR1B locus which are associated with fasting plasma glucose (FPG) and type 2 diabetes (T2D). 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), T2D 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 T2D patients (n=1,626) and controls (n=505), in the 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 T2D. The rs10830963-G allele increased the risk of i-IFG (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 to hepatic insulin resistance (P=0.017).

    Conclusions. The G-allele of MTNR1B rs10830963 increases risk of T2D 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

      • Received December 1, 2008.
      • Accepted March 12, 2009.

    This Article

    1. Published online before print March 26, 2009, doi: 10.2337/db08-1660
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