Association testing of common variants in the insulin receptor substrate-1 gene (IRS1) with type 2 diabetes.
OBJECTIVE
Activation of the insulin receptor substrate-1 (IRS1) is a key initial step in the insulin signalling pathway. Despite several reports of association of the G972R polymorphism in its gene IRS1 with type 2 diabetes, we and others have not observed this association in well-powered samples. However, other nearby variants might account for the putative association signal.


METHODS
We characterised the haplotype map of IRS1 and selected 20 markers designed to capture common variations in the region. We genotyped this comprehensive set of markers in several family-based and case-control samples of European descent totalling 12,129 subjects.


RESULTS
In an initial sample of 2,235 North American and Polish case-control pairs, the minor allele of the rs934167 polymorphism showed nominal evidence of association with type 2 diabetes (odds ratio [OR] 1.25, 95% CI 1.03-1.51, p = 0.03). This association showed a trend in the same direction in 7,659 Scandinavian samples (OR 1.16, 95% CI 0.96-1.39, p = 0.059). The combined OR was 1.20 (p = 0.008), but statistical correction for the number of variants examined yielded a p value of 0.086. We detected no differences across rs934167 genotypes in insulin-related quantitative traits.


CONCLUSIONS
Our data do not support an association of common variants in IRS1 with type 2 diabetes in populations of European descent.
Florez
J C
JC
Simches Research Building-CPZN 6820, Diabetes Unit/Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA. jcflorez@partners.org
Sjögren
M
M
Agapakis
C M
CM
Burtt
N P
NP
Almgren
P
P
Lindblad
U
U
Berglund
G
G
Tuomi
T
T
Gaudet
D
D
Daly
M J
MJ
Ardlie
K G
KG
Hirschhorn
J N
JN
Altshuler
D
D
Groop
L
L
D000368:Aged; D015992:Body Mass Index; D016022:Case-Control Studies; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D014644:Genetic Variation; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin / Q000502:physiology; D055504:Insulin Receptor Substrate Proteins; D008297:Male; D008875:Middle Aged; D010750:Phosphoproteins / Q000235:genetics*; D011044:Poland / Q000208:ethnology; D020641:Polymorphism, Single Nucleotide; D015398:Signal Transduction; D013548:Sweden / Q000208:ethnology; D014481:United States; D044465:White People / Q000235:genetics
C526292:IRS1 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D010750:Phosphoproteins