Abstract
Genome-wide association studies have identified common variants that only partially explain the genetic risk for type 2 diabetes (T2D). Using genome-wide association data from 1,376 French individuals, we identified 16,360 SNPs nominally associated with T2D and studied these SNPs in an independent sample of 4,977 French individuals. We then selected the 28 best hits for replication in 7,698 Danish subjects and identified 4 SNPs showing strong association with T2D, one of which (rs2943641, P = 9.3 × 10−12, OR = 1.19) was located adjacent to the insulin receptor substrate 1 gene (IRS1). Unlike previously reported T2D risk loci, which predominantly associate with impaired beta cell function, the C allele of rs2943641 was associated with insulin resistance and hyperinsulinemia in 14,358 French, Danish and Finnish participants from population-based cohorts; this allele was also associated with reduced basal levels of IRS1 protein and decreased insulin induction of IRS1-associated phosphatidylinositol-3-OH kinase activity in human skeletal muscle biopsies.
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Change history
13 September 2009
NOTE: In the version of this article initially published online, there were errors in the e-mail addresses of two of the corresponding authors. The correct e-mail address for Robert Sladek is robert.sladek@mcgill.ca; the correct e-mail address for Philippe Froguel is philippe.froguel@good.ibl.fr. These errors have been corrected for the print, PDF and HTML versions of this article.
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Acknowledgements
This work was funded by Genome Canada, Génome Québec and the Canada Foundation for Innovation. This work was also supported by the French Government (Agence Nationale de la Recherche), the French Region of Nord Pas De Calais (Contrat de Projets État-Région), and the following charities: Association Française des Diabétiques, Programme National de Recherche sur le Diabète and Association de Langue Française pour l'Etude du Diabète et des Maladies Métaboliques. The D.E.S.I.R. study has been supported by the Caisse Nationale d?Assurance Maladie des Travailleurs Salariés, Lilly, Novartis Pharma and Sanofi-Aventis, Institut National de la Santé et de la Recherche Médicale (INSERM) (Réseaux en Santé Publique, Interactions entre les déterminants de la santé), Association Diabète Risque Vasculaire, Fédération Française de Cardiologie, Fondation de France, Association de Langue Francaise pour l'Etude du Diabete et des Maladies Metaboliques, Office National Interprofessionnel des Vins, Ardix Medical, Bayer Diagnostics, Becton Dickinson, Cardionics, Merck Santé, Novo Nordisk, Pierre Fabre, Roche and Topcon. The D.E.S.I.R. Study Group: INSERM U780: B. Balkau, P. Ducimetière, E. Eschwège; INSERM U367: F. Alhenc-Gelas; Centre Hospitalier Universitaire 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. The NFBC 1986 study has been supported by the Oulu University Hospital, Finland, the Academy of Finland and the European Commission (Framework 5 award QLG1-CT-2000-01643). The Danish study was supported by grants from the Lundbeck Foundation Centre of Applied Medical Genomics for Personalized Disease Prediction, Prevention and Care (LUCAMP), the European Union (EUGENE2) grant LSHM-CT-2004-512013, EXGENESIS grant LSHM-CT-2004-005272, the Danish Diabetes Association and the Danish Agency for Science, Technology and Innovation, grant no. 271-06-0539. This study was supported in part by a grant from the European Union (Integrated Project EuroDia LSHM-CT-2006-518153 in the Framework Programme 6 [FP6] of the European Community). M.P. is the recipient of a Canadian Chair in diabetes and metabolism. R.S. is a Chercheur-boursier of the Fonds de la recherche en santé du Québec and the recipient of an MGH One Hundred and Seventy-Fifth Anniversary Award from Research Institute of the Montreal General Hospital Foundation. We thank L. Peltonen-Palotie for her contribution in DNA extraction and distribution; M. Deweider and F. Allegaert for the DNA bank management; R. Frechette, V. Catudal, D. Vincent, A. Forman, I.-L. Wantzin, T. Lorentzen, M. Stendal, M.H. Kristensen, T. Brunt and A.L. Nielsen for their technical or management assistance. Large-scale computations were performed using the Consortium Laval, Université du Québec, McGill and Eastern Quebec supercomputer facility. We are sincerely indebted to all subjects who participated in this study.
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B.B., G.C., P.E., S.H., M.-R.J., J.L., M.M., O.P., T.H., T.L., K.B.-J., C. Pisinger, A.P., A.R., A.S. and J.T. recruited and phenotyped patient cohorts. F.B., A.B., E.D., A. Montpetit and L.S. designed and performed genotyping studies. P.P., R.R.-M., A.V. and J.F.P.W. performed hyperinsulinemic and euglycemic clamp studies as well as studies of muscle biopsies. A.A., S.C., C.C.-P., A. Mazur, G.R., J.R., D.S. and L.S. analyzed genotyping data. A.A., S.C., C.D., P.F., D.M., O.P., C. Polychronakos, B.P., M.P., J.R., R.S. and M.V. wrote the first draft of the manuscript. R.S., P.F. and O.P. planned and coordinated the study. All authors contributed to the final version of the manuscript.
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Rung, J., Cauchi, S., Albrechtsen, A. et al. Genetic variant near IRS1 is associated with type 2 diabetes, insulin resistance and hyperinsulinemia. Nat Genet 41, 1110–1115 (2009). https://doi.org/10.1038/ng.443
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DOI: https://doi.org/10.1038/ng.443
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