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 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 Wojtaszewski, Allan Vaag, Torben Hansen, Constantin Polychronakos, Oluf Pedersen, Philippe Froguel, Robert Sladek

325 Citations (Scopus)

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 x 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
Journal	Nature Genetics
Volume	41
Issue number	10
Pages (from-to)	1110-1115
Number of pages	6
ISSN	1061-4036
DOIs	https://doi.org/10.1038/ng.443
Publication status	Published - 2009

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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

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, 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, J , 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

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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 x 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 Marjo-Riitta J{\"a}rvelin 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 J{\o}rgen Wojtaszewski and Allan Vaag and Torben Hansen and Constantin Polychronakos and Oluf Pedersen and Philippe Froguel and Robert Sladek",

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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

AU - Vaag, Allan

AU - Hansen, Torben

AU - Polychronakos, Constantin

AU - Pedersen, Oluf

AU - Froguel, Philippe

AU - Sladek, Robert

N1 - CURIS 2009 5200 136 Export Date: 4 November 2009Source: Scopus

PY - 2009

Y1 - 2009

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 x 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 x 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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DO - 10.1038/ng.443

M3 - Journal article

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SN - 1061-4036

VL - 41

SP - 1110

EP - 1115

JO - Nature: New biology

JF - Nature: New biology

IS - 10

ER -

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

Abstract

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