Analysis of novel risk loci for type 2 diabetes in a general French population: the D.E.S.I.R. study (original) (raw)

Abstract

Recently, Genome Wide Association (GWA) studies identified novel single nucleotide polymorphisms (SNPs), highly associated with type 2 diabetes (T2D) in several case-control studies of European descent. However, the impact of these markers on glucose homeostasis in a population-based study remains to be clarified.

The French prospective D.E.S.I.R. study (N = 4,707) was genotyped for 22 polymorphisms within 14 loci showing nominal to strong association with T2D in recently published GWA analyses (CDKAL1, IGFBP2, CDKN2A/2B, EXT2, HHEX, LOC646279, SLC30A8, MMP26, KCTD12, LDLR, CAMTA1, LOC38776, NGN3 and CXCR4). We assessed their effects on quantitative traits related to glucose homeostasis in 4,283 normoglycemic middle-aged participants at baseline and their contribution to T2D incidence during 9 years of follow-up.

Individuals carrying T2D risk alleles of CDKAL1 or SLC30A8 had lower fasting plasma insulin level (rs7756992 P = 0.003) or lower basal insulin secretion (rs13266634 P = 0.0005), respectively, than non-carriers. Furthermore, NGN3 and MMP26 risk alleles associated with higher fasting plasma glucose levels (rs10823406 P = 0.01 and rs2499953 P = 0.04, respectively). However, for these SNPs, only modest associations were found with a higher incidence of T2D: hazard ratios of 2.03 [1.00–4.11] for MMP26 (rs2499953 P = 0.05) and 1.33 [1.02–1.73] for NGN3 (rs10823406 P = 0.03).

We confirmed deleterious effects of SLC30A8, CDKAL1, NGN3 and MMP26 risk alleles on glucose homeostasis in the D.E.S.I.R. prospective cohort. However, in contrast to TCF7L2, the contribution of novel loci to T2D incidence seems only modest in the general middle-aged French population and should be replicated in larger cohorts.

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Acknowledgements

This work was partly supported by the French Government “Agence Nationale de la Recherche_”, and the charities: “_Association Française des Diabétiques” and “_Programme national de recherche sur le diabète_”. We thank Marianne Deweider and Frederic Allegaert for the DNA bank management. We are indebted to all subjects who participated to this study.

The D.E.S.I.R. study has been supported by CNAMTS, Lilly, Novartis Pharma and Sanofi-Aventis, by INSERM (Réseaux en Santé Publique, Interactions entre les determinants de la santé), by the Association Diabète Risque Vasculaire, the Fédération Française de Cardiologie, La Fondation de France, ALFEDIAM, ONIVINS, Ardix Medical, Bayer Diagnostics, Becton Dickinson, Cardionics, Merck Santé, Novo Nordisk, Pierre Fabre, Roche, Topcon.

The D.E.S.I.R. Study Group: INSERM U780: B. Balkau, P. Ducimetière, E. Eschwège; INSERM U367: F. Alhenc-Gelas; CHU D'Angers: Y. Gallois, A. Girault; Bichat Hospital: F. Fumeron, M. Marre; Medical Examination Services: Alençon, Angers, Caen, Chateauroux, Cholet, Le Mans, and Tours; Research Institute for General Medicine: J. Cogneau; General practitioners of the region; Cross-Regional Institute for Health: C. Born, E. Caces, M. Cailleau, J.G. Moreau, F. Rakotozafy, J. Tichet, S. Vol.

Duality of interest

The authors declare that there is no duality of interest.

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Authors and Affiliations

  1. CNRS 8090-Institute of Biology, Pasteur Institute, Lille, France
    Stéphane Cauchi, Christine Proença, Hélène Choquet, Stefan Gaget, Franck De Graeve, David Meyre, Martine Vaxillaire & Philippe Froguel
  2. René Diderot-Paris 7 University, Paris, France
    Michel Marre
  3. Department of Endocrinology-Diabetology and Nutrition, Bichat Claude Bernard Hospital, INSERM U695, Paris, France
    Michel Marre
  4. INSERM U780-IFR69, Villejuif, France
    Beverley Balkau
  5. University of Paris-Sud, Paris, France
    Beverley Balkau
  6. Regional Institute for Health, La Riche, France
    Jean Tichet
  7. Imperial College, Section of Genomic Medicine, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK
    Philippe Froguel

Authors

  1. Stéphane Cauchi
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  2. Christine Proença
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  3. Hélène Choquet
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  4. Stefan Gaget
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  5. Franck De Graeve
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  6. Michel Marre
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  7. Beverley Balkau
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  8. Jean Tichet
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  9. David Meyre
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  10. Martine Vaxillaire
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  11. Philippe Froguel
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D.E.S.I.R. Study Group

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Correspondence toPhilippe Froguel.

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Supplementary Table 1

Clinical characteristics of the D.E.S.I.R. population at baseline (DOC 36.0 KB)

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Cauchi, S., Proença, C., Choquet, H. et al. Analysis of novel risk loci for type 2 diabetes in a general French population: the D.E.S.I.R. study.J Mol Med 86, 341–348 (2008). https://doi.org/10.1007/s00109-007-0295-x

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