Letter abstract
Nature Genetics 41, 1110 - 1115 (2009)
Published online: 6 September 2009 | Corrected online: 13 September 2009 | doi:10.1038/ng.443
There is an Erratum (October 2009) associated with this Letter.
Genetic variant near IRS1 is associated with type 2 diabetes, insulin resistance and hyperinsulinemia
Johan Rung1,28,29, Stéphane Cauchi2,29, Anders Albrechtsen3,29, Lishuang Shen1,28, Ghislain Rocheleau1,4,28, Christine Cavalcanti-Proença2, François Bacot1, Beverley Balkau5, Alexandre Belisle1, Knut Borch-Johnsen6, Guillaume Charpentier7, Christian Dina2, Emmanuelle Durand2, Paul Elliott8, Samy Hadjadj9, Marjo-Riitta Järvelin8,10, Jaana Laitinen11, Torsten Lauritzen12, Michel Marre13, Alexander Mazur1, David Meyre2, Alexandre Montpetit1, Charlotta Pisinger14, Barry Posner15,16, Pernille Poulsen6, Anneli Pouta8,17, Marc Prentki18, Rasmus Ribel-Madsen6, Aimo Ruokonen19, Anelli Sandbaek12, David Serre1,28, Jean Tichet20, Martine Vaxillaire2, Jørgen F P Wojtaszewski21, Allan Vaag6,22, Torben Hansen23,24, Constantin Polychronakos4,25, Oluf Pedersen23,26, Philippe Froguel2,27 & Robert Sladek1,4,15
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.
- McGill University and Génome Québec Innovation Centre, Montréal, Canada.
- Centre National de la Recherche Scientifique–Unité Mixte de Recherche–8090, Institute of Biology and Lille 2 University, Pasteur Institute, Lille, France.
- Department of Biostatistics, University of Copenhagen, Copenhagen, Denmark.
- Department of Human Genetics, Faculty of Medicine, McGill University, Montreal, Canada.
- Institut National de la Santé et de la Recherche Médicale (INSERM), U780, Villejuif, France; and University Paris-Sud, Orsay, France.
- Steno Diabetes Center, Gentofte, Denmark.
- Endocrinology-Diabetology Unit, Corbeil-Essonnes Hospital, Corbeil-Essonnes, France.
- Department of Epidemiology and Public Health, Imperial College London, London, UK.
- Poitiers Hospital, Endocrinology and Diabetology, Centre d'Investigation Clinique INSERM 0801, INSERM U927, Université de Poitiers, Unité de Formation et de Recherche, Medecine Pharmacie, Poitiers, France.
- Institute of Health Sciences and Biocenter Oulu, University of Oulu, Oulu, Finland; and Department of Child and Adolescent Health, National Public Health Institute, Helsinki, Finland.
- Finnish Institute of Occupational Health, Helsinki, Finland.
- Department of General Practice, University of Aarhus, Aarhus C, Denmark.
- Department of Endocrinology, Diabetology and Nutrition, Bichat-Claude Bernard University Hospital, Assistance Publique des Hôpitaux de Paris, Paris, France; INSERM U695, Université Paris 7, Paris, France; Diderot University, Paris, France.
- Research Centre for Prevention and Health, Glostrup University Hospital, Glostrup, Denmark.
- Department of Medicine, Faculty of Medicine, McGill University, Montreal, Canada.
- Polypeptide Hormone Laboratory and Department of Anatomy and Cell Biology, McGill University, Montréal, Canada.
- Public Health Science and General Practice, University of Oulu, Oulu, Finland.
- Montreal Diabetes Research Center, Montreal, Canada; Molecular Nutrition Unit and the Department of Nutrition, University of Montréal and the Centre Hospitalier de l'Université de Montréal, Montréal, Canada.
- Department of Clinical Chemistry, University of Oulu, Oulu, Finland.
- Institut Interrégional pour la Santé, La Riche, France.
- Copenhagen Muscle Research Centre, Institute of Exercise and Sport Sciences, University of Copenhagen, Copenhagen NV, Denmark.
- Unit of Diabetes and Endocrinology, Department of Clinical Sciences, Malmö University Hospital, Lund University, Malmö, Sweden.
- Hagedorn Research Institute and Steno Diabetes Center, Gentofte, Denmark.
- Faculty of Health Science, University of Southern Denmark, Odense M, Denmark.
- Department of Pediatrics, Faculty of Medicine, McGill University, Montreal, Canada.
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen N, Denmark; and Faculty of Health Sciences, University of Aarhus, Aarhus C, Denmark.
- Centre and Department of Genomic Medicine, Hammersmith Hospital, Imperial College London, London, UK.
- Current addresses: EMBL–European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK (J.R.); The Hospital for Sick Children Research Institute, Toronto, Canada (L.S.); Prognomix Inc., Montreal, Canada (G.R.); Genomic Medicine Institute, Lerner Research Institute, Cleveland, Ohio, USA (D.S.).
- These authors contributed equally to this work.
Correspondence to: Oluf Pedersen23,26 e-mail: oluf@hagedorn.dk
Correspondence to: Philippe Froguel2,27 e-mail: philippe.froguel@good.ibl.fr
Correspondence to: Robert Sladek1,4,15 e-mail: robert.sladek@mcgill.ca
