Genetic variant near IRS1 is associated with type 2 diabetes, insulin resistance and hyperinsulinemia.
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.
Rung
Johan
J
McGill University and Génome Québec Innovation Centre, Montréal, Canada.
Cauchi
Stéphane
S
Albrechtsen
Anders
A
Shen
Lishuang
L
Rocheleau
Ghislain
G
Cavalcanti-Proença
Christine
C
Bacot
François
F
Balkau
Beverley
B
Belisle
Alexandre
A
Borch-Johnsen
Knut
K
Charpentier
Guillaume
G
Dina
Christian
C
Durand
Emmanuelle
E
Elliott
Paul
P
Hadjadj
Samy
S
Järvelin
Marjo-Riitta
MR
Laitinen
Jaana
J
Lauritzen
Torsten
T
Marre
Michel
M
Mazur
Alexander
A
Meyre
David
D
Montpetit
Alexandre
A
Pisinger
Charlotta
C
Posner
Barry
B
Poulsen
Pernille
P
Pouta
Anneli
A
Prentki
Marc
M
Ribel-Madsen
Rasmus
R
Ruokonen
Aimo
A
Sandbaek
Anelli
A
Serre
David
D
Tichet
Jean
J
Vaxillaire
Martine
M
Wojtaszewski
Jørgen F P
JF
Vaag
Allan
A
Hansen
Torben
T
Polychronakos
Constantin
C
Pedersen
Oluf
O
Froguel
Philippe
P
Sladek
Robert
R
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
D055504:Insulin Receptor Substrate Proteins; D019869:Phosphatidylinositol 3-Kinases; C526292:IRS1 protein, human