Genetic variant near IRS1 is associated with type 2 diabetes, insulin resistance and hyperinsulinemia

Johan Rung; Stéphane Cauchi; Anders Albrechtsen; Lishuang Shen; Ghislain Rocheleau; Christine Cavalcanti-Proença; François Bacot; Beverley Balkau; Alexandre Belisle; Knut Borch-Johnsen; Guillaume Charpentier; Christian Dina; Emmanuelle Durand; Paul Elliott; Samy Hadjadj; Marjo Riitta Järvelin; Jaana Laitinen; Torsten Lauritzen; Michel Marre; Alexander Mazur; David Meyre; Alexandre Montpetit; Charlotta Pisinger; Barry Posner; Pernille Poulsen; Anneli Pouta; Marc Prentki; Rasmus Ribel-Madsen; Aimo Ruokonen; Anelli Sandbaek; David Serre; Jean Tichet; Martine Vaxillaire; Jørgen F.P. Wojtaszewski; Allan Vaag; Torben Hansen; Constantin Polychronakos; Oluf Pedersen; Philippe Froguel; Robert Sladek

doi:10.1038/ng.443

Genetic variant near IRS1 is associated with type 2 diabetes, insulin resistance and hyperinsulinemia

Johan Rung, Stéphane Cauchi, Anders Albrechtsen, Lishuang Shen, Ghislain Rocheleau, Christine Cavalcanti-Proença, François Bacot, Beverley Balkau, Alexandre Belisle, Knut Borch-Johnsen, Guillaume Charpentier, Christian Dina, Emmanuelle Durand, Paul Elliott, Samy Hadjadj, Marjo Riitta Järvelin, Jaana Laitinen, Torsten Lauritzen, Michel Marre, Alexander MazurDavid Meyre, Alexandre Montpetit, Charlotta Pisinger, Barry Posner, Pernille Poulsen, Anneli Pouta, Marc Prentki, Rasmus Ribel-Madsen, Aimo Ruokonen, Anelli Sandbaek, David Serre, Jean Tichet, Martine Vaxillaire, Jørgen F.P. Wojtaszewski, Allan Vaag, Torben Hansen, Constantin Polychronakos, Oluf Pedersen, Philippe Froguel, Robert Sladek

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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.

Original language	English
Pages (from-to)	1110-1115
Number of pages	6
Journal	Nature Genetics
Volume	41
Issue number	10
DOIs	https://doi.org/10.1038/ng.443
State	Published - Oct 2009
Externally published	Yes

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Rung, J., Cauchi, S., Albrechtsen, A., Shen, L., Rocheleau, G., Cavalcanti-Proença, C., Bacot, F., Balkau, B., Belisle, A., Borch-Johnsen, K., Charpentier, G., Dina, C., Durand, E., Elliott, P., Hadjadj, S., Järvelin, M. R., Laitinen, J., Lauritzen, T., Marre, M., ... Sladek, R. (2009). Genetic variant near IRS1 is associated with type 2 diabetes, insulin resistance and hyperinsulinemia. Nature Genetics, 41(10), 1110-1115. https://doi.org/10.1038/ng.443

@article{543316d23db54271bbca308f693fdae7,

title = "Genetic variant near IRS1 is associated with type 2 diabetes, insulin resistance and hyperinsulinemia",

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.",

author = "Johan Rung and St{\'e}phane Cauchi and Anders Albrechtsen and Lishuang Shen and Ghislain Rocheleau and Christine Cavalcanti-Proen{\c c}a and Fran{\c c}ois Bacot and Beverley Balkau and Alexandre Belisle and Knut Borch-Johnsen and Guillaume Charpentier and Christian Dina and Emmanuelle Durand and Paul Elliott and Samy Hadjadj and J{\"a}rvelin, {Marjo Riitta} and Jaana Laitinen and Torsten Lauritzen and Michel Marre and Alexander Mazur and David Meyre and Alexandre Montpetit and Charlotta Pisinger and Barry Posner and Pernille Poulsen and Anneli Pouta and Marc Prentki and Rasmus Ribel-Madsen and Aimo Ruokonen and Anelli Sandbaek and David Serre and Jean Tichet and Martine Vaxillaire and Wojtaszewski, {J{\o}rgen F.P.} and Allan Vaag and Torben Hansen and Constantin Polychronakos and Oluf Pedersen and Philippe Froguel and Robert Sladek",

note = "Funding Information: This work was funded by Genome Canada, G{\'e}nome Qu{\'e}bec 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 {\'E}tat-R{\'e}gion), and the following charities: Association Fran{\c c}aise des Diab{\'e}tiques, Programme National de Recherche sur le Diab{\`e}te and Association de Langue Fran{\c c}aise pour l{\textquoteright}Etude du Diab{\`e}te et des Maladies M{\'e}taboliques. The D.E.S.I.R. study has been supported by the Caisse Nationale d{\textquoteright}Assurance Maladie des Travailleurs Salari{\'e}s, Lilly, Novartis Pharma and Sanofi-Aventis, Institut National de la Sant{\'e} et de la Recherche M{\'e}dicale (INSERM) (R{\'e}seaux en Sant{\'e} Publique, Interactions entre les d{\'e}terminants de la sant{\'e}), Association Diab{\`e}te Risque Vasculaire, F{\'e}d{\'e}ration Fran{\c c}aise de Cardiologie, Fondation de France, Association de Langue Francaise pour l{\textquoteright}Etude du Diabete et des Maladies Metaboliques, Office National Interprofessionnel des Vins, Ardix Medical, Bayer Diagnostics, Becton Dickinson, Cardionics, Merck Sant{\'e}, Novo Nordisk, Pierre Fabre, Roche and Topcon. The D.E.S.I.R. Study Group: INSERM U780: B. Balkau, P. Ducimeti{\`e}re, E. Eschw{\`e}ge; INSERM U367: F. Alhenc-Gelas; Centre Hospitalier Universitaire D{\textquoteright}Angers: Y. Gallois, A. Girault; Bichat Hospital: F. Fumeron, M. Marre; Medical Examination Services: Alen{\c c}on, 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 sant{\'e} du Qu{\'e}bec 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, Universit{\'e} du Qu{\'e}bec, McGill and Eastern Quebec supercomputer facility. We are sincerely indebted to all subjects who participated in this study.",

year = "2009",

month = oct,

doi = "10.1038/ng.443",

language = "English",

volume = "41",

pages = "1110--1115",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "10",

}

Rung, J, Cauchi, S, Albrechtsen, A, Shen, L, Rocheleau, G, Cavalcanti-Proença, C, Bacot, F, Balkau, B, Belisle, A, Borch-Johnsen, K, Charpentier, G, Dina, C, Durand, E, Elliott, P, Hadjadj, S, Järvelin, MR, Laitinen, J, Lauritzen, T, Marre, M, Mazur, A, Meyre, D, Montpetit, A, Pisinger, C, Posner, B, Poulsen, P, Pouta, A, Prentki, M, Ribel-Madsen, R, Ruokonen, A, Sandbaek, A, Serre, D, Tichet, J, Vaxillaire, M, Wojtaszewski, JFP, Vaag, A, Hansen, T, Polychronakos, C, Pedersen, O, Froguel, P & Sladek, R 2009, 'Genetic variant near IRS1 is associated with type 2 diabetes, insulin resistance and hyperinsulinemia', Nature Genetics, vol. 41, no. 10, pp. 1110-1115. https://doi.org/10.1038/ng.443

TY - JOUR

T1 - Genetic variant near IRS1 is associated with type 2 diabetes, insulin resistance and hyperinsulinemia

AU - Rung, Johan

AU - Cauchi, Stéphane

AU - Albrechtsen, Anders

AU - Shen, Lishuang

AU - Rocheleau, Ghislain

AU - Cavalcanti-Proença, Christine

AU - Bacot, François

AU - Balkau, Beverley

AU - Belisle, Alexandre

AU - Borch-Johnsen, Knut

AU - Charpentier, Guillaume

AU - Dina, Christian

AU - Durand, Emmanuelle

AU - Elliott, Paul

AU - Hadjadj, Samy

AU - Järvelin, Marjo Riitta

AU - Laitinen, Jaana

AU - Lauritzen, Torsten

AU - Marre, Michel

AU - Mazur, Alexander

AU - Meyre, David

AU - Montpetit, Alexandre

AU - Pisinger, Charlotta

AU - Posner, Barry

AU - Poulsen, Pernille

AU - Pouta, Anneli

AU - Prentki, Marc

AU - Ribel-Madsen, Rasmus

AU - Ruokonen, Aimo

AU - Sandbaek, Anelli

AU - Serre, David

AU - Tichet, Jean

AU - Vaxillaire, Martine

AU - Wojtaszewski, Jørgen F.P.

AU - Vaag, Allan

AU - Hansen, Torben

AU - Polychronakos, Constantin

AU - Pedersen, Oluf

AU - Froguel, Philippe

AU - Sladek, Robert

N1 - Funding Information: 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.

PY - 2009/10

Y1 - 2009/10

N2 - 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.

AB - 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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U2 - 10.1038/ng.443

DO - 10.1038/ng.443

M3 - Article

C2 - 19734900

AN - SCOPUS:70349557826

SN - 1061-4036

VL - 41

SP - 1110

EP - 1115

JO - Nature Genetics

JF - Nature Genetics

IS - 10

ER -

Genetic variant near IRS1 is associated with type 2 diabetes, insulin resistance and hyperinsulinemia

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