No association between a polymorphic variant of the IRS-1 gene and prostate cancer risk.
OBJECTIVE
Insulin receptor substrate-1 (IRS-1) acts as a docking protein between the insulin-like growth factor-1 (IGF-1) receptor and intracellular signaling molecules in the IGF-1 signaling pathway. Accumulating data support a role of IGF-1 in prostate carcinogenesis. We assessed the influence of the most common IRS-1 gene polymorphism (Gly972Arg) on prostate cancer risk, alone and in combination with IGF-1 and other components in the IGF-1 signaling pathway.


METHODS
In a nested case-control study within the Physicians' Health Study, the IRS-1 polymorphism was assayed from prospectively collected samples from 564 incident prostate cancer cases and 758 controls matched on age and smoking. We calculated relative risks (RR) and 95% confidence intervals (CI) using conditional logistic regression.


RESULTS
Among the controls, 0.8% were homozygous (AA) and 12% were heterozygous (GA) for the polymorphic allele. There was no association between carriage of the A allele and total prostate cancer risk (RR = 1.1 95% CI = 0.8-1.5), advanced disease (stage C or D or lethal prostate cancer, RR = 1.3 95% CI = 0.8-2.3), or plasma IGF-1 levels. We explored possible interactions with body mass index and components in the IGF-1 pathway including IGFBP3, PI3k, and PTEN but none of these factors influenced the relation between IRS-1 genotype and prostate cancer risk.


CONCLUSIONS
Our data do not support an association between carriage of the variant IRS-1 gene and prostate cancer risk.
Fall
K
K
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. katja.fall@ki.se
Stark
J R
JR
Mucci
L A
LA
Chan
J
J
Stampfer
M J
MJ
Kurth
T
T
Febbo
P G
PG
Kantoff
P
P
Ma
J
J
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000368:Aged; D016022:Case-Control Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D018972:Insulin-Like Growth Factor Binding Protein 3; D018969:Insulin-Like Growth Factor Binding Proteins / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011110:Polymorphism, Genetic / Q000235:genetics*; D011446:Prospective Studies; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
D048868:Adaptor Proteins, Signal Transducing; C515497:IGFBP3 protein, human; C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; D018972:Insulin-Like Growth Factor Binding Protein 3; D018969:Insulin-Like Growth Factor Binding Proteins; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases; D051059:PTEN Phosphohydrolase