title: Nitric oxide synthase gene polymorphisms and prostate cancer risk.
abstract: Nitric oxide (NO) induces cytotoxicity and angiogenesis, and may play a role in prostate carcinogenesis, potentially modulated by environmental exposures. We evaluated the association of prostate cancer with genetic polymorphisms in two genes related to intracellular NO: NOS2A [inducible nitric oxide synthase (NOS); -2892T>C, Ex16 + 14C>T (S608L), IVS16 + 88T>G and IVS20 + 524G>A] and NOS3 [endothelial NOS; IVS1-762C>T, Ex7-43C>T (D258D), IVS7-26A>G, Ex8-63G>T (E298D) and IVS15-62G>T]. Prostate cancer cases (n = 1320) from the screening arm of the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial were frequency matched to controls (n = 1842), by age, race, time since initial screening and year of blood draw. An antioxidant score [range 3-12; low (3-7) versus high (8-12)] was created by summing the quartile levels of vitamin E, beta-carotene and lycopene, which were coded from 1 to 4, respectively. The global tests for all eight single-nucleotide polymorphisms (SNPs) (excluding NOS2A-2892T>C, with low minor allele frequency) were statistically significant for prostate cancer (P = 0.005), especially for aggressive cancer (stage III-IV or Gleason score > or = 7) (P = 0.01). The NOS2A IVS16 + 88 GT/TT was associated with increased prostate cancer risk (odds ratio = 1.24, 95% confidence interval = 1.00-1.54), whereas the IVS20 + 524 AG/GG was associated with decreased risk (0.77, 0.66-0.90). The NOS3 IVS7-26GG was associated with increased prostate cancer risk (1.33, 1.07-1.64). All these SNPs showed significant associations with aggressive cancer and not for non-aggressive cancer. In the evaluation of effect modification, the effect of the NOS2A IVS16 + 88 GT/TT on aggressive cancer was stronger among subjects with higher antioxidant intake (1.61, 1.18-2.19; P(interaction) = 0.01). Our results suggest that NOS gene polymorphisms are genetic susceptibility factors for aggressive prostate cancer.
authors.affiliation: Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA. leekyou@mail.nih.gov
authors.forename: Kyoung-Mu
authors.initials: KM
authors.lastname: Lee
authors.forename: Daehee
authors.initials: D
authors.lastname: Kang
authors.forename: Sue Kyung
authors.initials: SK
authors.lastname: Park
authors.forename: Sonja I
authors.initials: SI
authors.lastname: Berndt
authors.forename: Douglas
authors.initials: D
authors.lastname: Reding
authors.forename: Nilanjan
authors.initials: N
authors.lastname: Chatterjee
authors.forename: Stephen
authors.initials: S
authors.lastname: Chanock
authors.forename: Wen-Yi
authors.initials: WY
authors.lastname: Huang
authors.forename: Richard B
authors.initials: RB
authors.lastname: Hayes
mesh_terms: D000368:Aged; D000975:Antioxidants / Q000008:administration & dosage*; D002338:Carotenoids / Q000008:administration & dosage; D016022:Case-Control Studies; D005838:Genotype; D006801:Humans; D000077276:Lycopene; D008297:Male; D008875:Middle Aged; D052247:Nitric Oxide Synthase Type II / Q000235:genetics*; D052250:Nitric Oxide Synthase Type III / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000097:blood / Q000235:genetics* / Q000517:prevention & control; D012307:Risk Factors; D014810:Vitamin E / Q000008:administration & dosage; D019207:beta Carotene / Q000008:administration & dosage
chemical_list: D000975:Antioxidants; D019207:beta Carotene; D014810:Vitamin E; D002338:Carotenoids; C496319:NOS2 protein, human; C496314:NOS3 protein, human; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D000077276:Lycopene