Nitric oxide synthase gene polymorphisms and prostate cancer risk
Nitric oxide synthase gene polymorphisms and prostate cancer risk
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DOI：
10.1093/carcin/bgp028
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发表时间：
2009-04-01
期刊：
影响因子：
4.7
通讯作者：
Hayes, Richard B.
中科院分区：
文献类型：
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作者：
Lee, Kyoung-Mu;Kang, Daehee;Hayes, Richard B.
一氧化氮(NO)诱导细胞毒性和血管生成，并可能在前列腺癌的发生中发挥作用，可能受环境暴露的调节。我们评估了前列腺癌与细胞内NO相关的两个基因：NOS2A[诱导型一氧化氮合酶(NOS)；-2892T>；C，EX16+14C>；T(S608L)，IVS16+88T>；G和IVS20+524G>；A]和NOS3[内皮NOS；IVS1-762C>；T，EX7-43C>；T(D258D)，IVS7-26A>；G，EX8-63G>；T(E298D)和IVS15-62G>；T]的遗传多态与前列腺癌的关系。来自前列腺癌、肺癌、结直肠癌和卵巢癌筛查试验的前列腺癌病例(n=1320)与对照组(n=1842)按年龄、种族、首次筛查开始时间和采血年份进行频率匹配。通过将维生素E、β-胡萝卜素和番茄红素的四分位数水平相加，得出抗氧化剂得分[范围3-12；低(3-7)对高(8-12)]，分别编码为1到4。所有8个单核苷酸多态(不包括NOS2A2892T和Gt；C，低等位基因频率)在前列腺癌(P=0.005)，特别是对侵袭性癌症(III-IV期或Gleason Score>；=7)有统计学意义(P=0.01)。NOS2AIVS16+88GT/TT与前列腺癌风险增加相关(优势比=1.24，95%可信区间=1.00~1.54)，而IVS20+524AG/GG与前列腺癌风险降低相关(0.77，0.66~0.90)。NOS3 IVS7-26GG与前列腺癌风险增加相关(1.33，1.07-1.64)。所有这些SNP都显示出与侵袭性癌症显著相关，而与非侵袭性癌症无关。在效果修正评价中，NOS2AIVS16+88GT/TT在抗氧化剂摄入量较高的受试者中对侵袭性癌症的影响更强(1.61，1.18~2.19；P交互作用=0.01)。提示一氧化氮合酶基因多态性是侵袭性前列腺癌的遗传易感因素。
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 >= 7) (P = 0.01). The NOS2A IVS16 + 88 GT/TT was associated with increased prostate caner 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 caner 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.