Background: Nitric oxide synthases (NOS) are a family of enzymes responsible for the generation of nitric oxide produced during chronic inflammation and other mechanisms involving oxidative stress, which may play an important role in prostate carcinogenesis. Also, NOS are expressed in the human prostate. We investigated the association between selected genetic polymorphisms in NOS3 (endothelial NOS) and NOS2 (iNOS) and prostate cancer. Method: Cases and controls were selected from male participants in the screening arm of the Prostate, Lung, Colorectal, and Ovarian Cancer (PLCO) Screening Trial, with prostate cancer cases (n= 484) frequency matched to controls (n= 617), by age, race (whites, 1:1.2 and blacks, 1:4), time since initial screening, and year of blood draw. Cases included 277 with clinically significant disease (Stage III - IV or Gleason’s Grade>=7). Four SNPs were genotyped: (NOS3 Ex8-63G>T (E298D), NOS3 IVS7-26A>G, NOS2 IVS20+524G>A, NOS2 Ex16+14T>C (S608L), by TaqMan assay. Conditional logistic regression was used to evaluate the association between genetic polymorphisms and prostate cancer. Results: Overall, no statistically significant associations were observed between the four polymorphisms and prostate cancer. The NOS3 IVS7-26 G allele was associated with clinically significant prostate cancer in white men (OR=1.55, 95% CI = 1.10 - 2.19), compared to the AA genotype. Risk for clinically significant prostate cancer also increased among white men with NOS3 Ex8-63 GG genotype (OR=1.32, 95% CI=0.97-1.81). Carriers of both the NOS3 IVS7-26 G allele and the NOS3 Ex8-63 GG genotype had 1.7 fold increased risk of clinically significant prostate cancer (95% CI = 1.13 - 2.55). Conclusions: These results suggest that genetic polymorphisms of NOS3 are associated with risk of prostate cancer, particularly with clinically important disease.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]