Association testing in 9,000 people fails to confirm the association of the insulin receptor substrate-1 G972R polymorphism with type 2 diabetes.
The insulin receptor substrate (IRS)-1 is an important component of the insulin signal transduction cascade. Several reports suggest that a Gly-->Arg change in codon 972 is associated with type 2 diabetes and related traits, and a recent meta-analysis reported a modest but nominally significant association with type 2 diabetes (odds ratio [OR] 1.25 in favor of carriers of the Arg allele [95% CI 1.05-1.48). To test the reproducibility of the model in a recent meta-analysis, we examined genotype-phenotype correlation in three large Caucasian samples (not previously reported for this variant) totaling 9,000 individuals (estimated to have >95% power to obtain a P < 0.05 for the OR of 1.25 estimated in the meta-analysis). In our combined sample, comprising 4,279 case and 3,532 control subjects, as well as 1,189 siblings discordant for type 2 diabetes, G972R was not associated with type 2 diabetes (OR 0.96 [0.84-1.10], P = 0.60). Genotype at G972R had no significant effect on various measures of insulin secretion or insulin resistance in a set of Scandinavian samples in whom we had detailed phenotypic data. In contrast, the well-documented associations of peroxisome proliferator-activated receptor gamma P12A and Kir6.2 E23K with type 2 diabetes are both robustly observed in these 9,000 subjects, including an additional (previously unpublished) confirmation of Kir6.2 E23K and type 2 diabetes in the Polish and North American samples (combined OR 1.15 [1.05-1.26], P = 0.001). Despite genotyping 9,000 people and >95% power to reproduce the estimated OR from the recent meta-analysis, we were unable to replicate the association of the IRS-1 G972R polymorphism with type 2 diabetes.
Florez
Jose C
JC
Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
Sjögren
Marketa
M
Burtt
Noël
N
Orho-Melander
Marju
M
Schayer
Steve
S
Sun
Maria
M
Almgren
Peter
P
Lindblad
Ulf
U
Tuomi
Tiinamaija
T
Gaudet
Daniel
D
Hudson
Thomas J
TJ
Daly
Mark J
MJ
Ardlie
Kristin G
KG
Hirschhorn
Joel N
JN
Altshuler
David
D
Groop
Leif
L
D019943:Amino Acid Substitution; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D010641:Phenotype; D010750:Phosphoproteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012537:Scandinavian and Nordic Countries; D035781:Siblings; D044465:White People / Q000235:genetics
C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; D010750:Phosphoproteins