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.
authors.affiliation: McGill University and Génome Québec Innovation Centre, Montréal, Canada.
authors.forename: Johan
authors.initials: J
authors.lastname: Rung
authors.forename: Stéphane
authors.initials: S
authors.lastname: Cauchi
authors.forename: Anders
authors.initials: A
authors.lastname: Albrechtsen
authors.forename: Lishuang
authors.initials: L
authors.lastname: Shen
authors.forename: Ghislain
authors.initials: G
authors.lastname: Rocheleau
authors.forename: Christine
authors.initials: C
authors.lastname: Cavalcanti-Proença
authors.forename: François
authors.initials: F
authors.lastname: Bacot
authors.forename: Beverley
authors.initials: B
authors.lastname: Balkau
authors.forename: Alexandre
authors.initials: A
authors.lastname: Belisle
authors.forename: Knut
authors.initials: K
authors.lastname: Borch-Johnsen
authors.forename: Guillaume
authors.initials: G
authors.lastname: Charpentier
authors.forename: Christian
authors.initials: C
authors.lastname: Dina
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Durand
authors.forename: Paul
authors.initials: P
authors.lastname: Elliott
authors.forename: Samy
authors.initials: S
authors.lastname: Hadjadj
authors.forename: Marjo-Riitta
authors.initials: MR
authors.lastname: Järvelin
authors.forename: Jaana
authors.initials: J
authors.lastname: Laitinen
authors.forename: Torsten
authors.initials: T
authors.lastname: Lauritzen
authors.forename: Michel
authors.initials: M
authors.lastname: Marre
authors.forename: Alexander
authors.initials: A
authors.lastname: Mazur
authors.forename: David
authors.initials: D
authors.lastname: Meyre
authors.forename: Alexandre
authors.initials: A
authors.lastname: Montpetit
authors.forename: Charlotta
authors.initials: C
authors.lastname: Pisinger
authors.forename: Barry
authors.initials: B
authors.lastname: Posner
authors.forename: Pernille
authors.initials: P
authors.lastname: Poulsen
authors.forename: Anneli
authors.initials: A
authors.lastname: Pouta
authors.forename: Marc
authors.initials: M
authors.lastname: Prentki
authors.forename: Rasmus
authors.initials: R
authors.lastname: Ribel-Madsen
authors.forename: Aimo
authors.initials: A
authors.lastname: Ruokonen
authors.forename: Anelli
authors.initials: A
authors.lastname: Sandbaek
authors.forename: David
authors.initials: D
authors.lastname: Serre
authors.forename: Jean
authors.initials: J
authors.lastname: Tichet
authors.forename: Martine
authors.initials: M
authors.lastname: Vaxillaire
authors.forename: Jørgen F P
authors.initials: JF
authors.lastname: Wojtaszewski
authors.forename: Allan
authors.initials: A
authors.lastname: Vaag
authors.forename: Torben
authors.initials: T
authors.lastname: Hansen
authors.forename: Constantin
authors.initials: C
authors.lastname: Polychronakos
authors.forename: Oluf
authors.initials: O
authors.lastname: Pedersen
authors.forename: Philippe
authors.initials: P
authors.lastname: Froguel
authors.forename: Robert
authors.initials: R
authors.lastname: Sladek
mesh_terms: D000328:Adult; D000483:Alleles; D001706:Biopsy; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006801:Humans; D006946:Hyperinsulinism / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics*; D007333:Insulin Resistance; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D044465:White People / Q000235:genetics
chemical_list: D055504:Insulin Receptor Substrate Proteins; D019869:Phosphatidylinositol 3-Kinases; C526292:IRS1 protein, human