CYP19A1 genetic variation in relation to prostate cancer risk and circulating sex hormone concentrations in men from the Breast and Prostate Cancer Cohort Consortium.
CYP19A1 genetic variation in relation to prostate cancer risk and circulating sex hormone concentrations in men from the Breast and Prostate Cancer Cohort Consortium.
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DOI：
10.1158/1055-9965.epi-09-0496
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发表时间：
2009-10
期刊：
影响因子：
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通讯作者：
Hunter DJ
中科院分区：
文献类型：
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作者：
Travis RC;Schumacher F;Hirschhorn JN;Kraft P;Allen NE;Albanes D;Berglund G;Berndt SI;Boeing H;Bueno-de-Mesquita HB;Calle EE;Chanock S;Dunning AM;Hayes R;Feigelson HS;Gaziano JM;Giovannucci E;Haiman CA;Henderson BE;Kaaks R;Kolonel LN;Ma J;Rodriguez L;Riboli E;Stampfer M;Stram DO;Thun MJ;Tjønneland A;Trichopoulos D;Vineis P;Virtamo J;Le Marchand L;Hunter DJ
性激素，特别是雄激素，对前列腺的生长很重要，并与前列腺癌的发生有关，但内源性类固醇激素水平的决定因素仍然知之甚少。双胞胎研究表明，性激素循环浓度的遗传成分，虽然类固醇激素基因变异与前列腺癌的流行病学证据是有限的。在这里，我们报告了一项由乳腺癌和前列腺癌队列联盟（BPC 3）进行的关于CYP 19 A1基因座遗传变异与前列腺癌风险和男性循环类固醇激素浓度的综合研究的结果，这是一项大型合作前瞻性研究。BPC 3通过靶向重测序和密集基因分型系统地表征了CYP 19 A1的变异;选择单倍型标记单核苷酸多态性（htSNP），有效预测美国和欧洲白人，拉丁美洲人，日裔美国人和夏威夷土著人的常见变异;并在8，166例前列腺癌病例和9，079例研究，年龄和种族匹配对照中对这些htSNP进行了基因分型。CYP 19 A1 htSNPs，两种常见的错义变异和常见的单倍型与前列腺癌的风险没有显著相关。然而，连锁不平衡区3和4中的几个htSNPs与男性雌二醇浓度的5-10%差异显著相关（两个SNP单倍型rs749292-rs727479（A-A）与非携带者的每拷贝相关性; P=1 × 10−5），并且与游离睾酮浓度的相反，尽管变化不太显著。这些结果表明，尽管以htSNPs为特征的CYP 19 A1的生殖系变异在男性性激素浓度方面产生了可测量的差异，但它们并不会显著影响前列腺癌的风险。
Sex hormones, in particular the androgens, are important for the growth of the prostate gland and have been implicated in prostate cancer carcinogenesis, yet the determinants of endogenous steroid hormone levels remain poorly understood. Twin studies suggest a heritable component for circulating concentrations of sex hormones, although epidemiological evidence linking steroid hormone gene variants to prostate cancer is limited. Here we report on findings from a comprehensive study of genetic variation at the CYP19A1 locus in relation to prostate cancer risk and to circulating steroid hormone concentrations in men by the Breast and Prostate Cancer Cohort Consortium (BPC3), a large collaborative prospective study. The BPC3 systematically characterised variation in CYP19A1 by targeted resequencing and dense genotyping; selected haplotype-tagging single nucleotide polymorphisms (htSNPs) that efficiently predict common variants in U.S. and European whites, Latinos, Japanese Americans, and Native Hawaiians; and genotyped these htSNPs in 8,166 prostate cancer cases and 9,079 study-, age-, and ethnicity-matched controls. CYP19A1 htSNPs, two common missense variants and common haplotypes were not significantly associated with risk of prostate cancer. However, several htSNPs in linkage disequilibrium blocks 3 and 4 were significantly associated with a 5–10% difference in estradiol concentrations in men (association per copy of the two-SNP haplotype rs749292–rs727479 (A–A) versus noncarriers; P=1 × 10−5), and withinverse, although less marked changes, in free testosterone concentrations. These results suggest that although germline variation in CYP19A1 characterised by the htSNPs produces measurable differences in sex hormone concentrations in men, they do not substantially influence risk for prostate cancer.