Association of mis-sense substitution in SRD5A2 gene with prostate cancer in African-American and Hispanic men in Los Angeles, USA
Association of mis-sense substitution in SRD5A2 gene with prostate cancer in African-American and Hispanic men in Los Angeles, USA
复制标题
DOI：
10.1016/s0140-6736(98)11282-5
复制
发表时间：
1999-09-18
期刊：
影响因子：
168.9
通讯作者：
Reichardt, JKV
中科院分区：
文献类型：
--
作者：
Makridakis, NM;Ross, RK;Reichardt, JKV
背景前列腺癌在较发达国家是一种非常常见的疾病，但其病因很大程度上尚不清楚。它是一种雄激素依赖性癌症，并且雄激素被认为在该疾病的易感性中具有重要作用。因此，雄激素代谢基因的变异可能会影响这种疾病的风险。方法我们从一项大型前瞻性队列研究（夏威夷-洛杉矶多种族队列研究）中筛选了 216 名非裔美国人和 172 名西班牙裔前列腺癌男性，以及 261 名非裔美国人和 200 名西班牙裔健康男性（对照），以检测人类前列腺（或 II 型）类固醇 5 α-还原酶的错义替代。 (SRD5A2) 基因，其产物控制睾酮代谢活化为二氢睾酮。这种错义取代导致密码子 49 处的丙氨酸残基被苏氨酸 (A49T) 取代。我们还在 SRD5A2 cDNA 中重建了这种突变，并在哺乳动物组织培养细胞中过表达该酶。结果发现，SRD5A2 基因中的 A49T 氨基酸替换使非裔美国男性患临床重大疾病的风险增加了 7.2 倍（95% CI=2.17-27.91；p=0.001），使西班牙裔男性患临床重大疾病的风险增加了 3.6 倍（1.09-12.27；p=0.001）。 p=0.04）。突变酶具有比正常酶更高的体外 V-max（9.9 vs 1.9 nmol min(-1) mg(-1)）。 解释 SRD5A2 基因的 A49T 变体可能是洛杉矶非裔美国人和西班牙裔男性前列腺癌发病率的重要因素。我们估计，在两个人群中，由于这种氨基酸替代导致临床显着疾病的人群归因风险约为 8%。这种变体类固醇 5 α 还原酶催化睾酮向二氢睾酮的转化增加可能是风险增加的原因。
Background Prostate cancer is a very common disease in more-developed countries, but its cause is largely unknown. It is an androgen-dependent cancer, and androgens have been proposed as having a substantial role in predisposition to the disease. Thus, variations in androgen metabolism genes may affect risk of this disease,Methods We screened 216 African-American and 172 Hispanic men with prostate cancer, and 261 African-American and 200 Hispanic healthy men (controls), from a large prospective cohort study (the Hawaii-Los Angeles Multiethnic Cohort Study) for a mis-sense substitution in the human prostatic (or type II) steroid 5 alpha-reductase (SRD5A2) gene, the product of which controls metabolic activation of testosterone to dihydrotestosterone. This mis-sense substitution results in an alanine residue at codon 49 being replaced with threonine (A49T). We also reconstructed this mutation in the SRD5A2 cDNA, and overexpressed the enzyme in mammalian tissue culture cells,Findings The A49T aminoacid substitution in the SRD5A2 gene increased the risk of clinically significant disease 7.2-fold in African-American men (95% CI=2.17-27.91; p=0.001) and 3.6-fold in Hispanic men (1.09-12.27; p=0.04). The mutant enzyme had a higher in-vitro V-max than the normal enzyme (9.9 vs 1.9 nmol min(-1) mg(-1)).Interpretation The A49T variant of the SRD5A2 gene may be a significant contributor to the incidence of prostate cancer in African-American and Hispanic men in Los Angeles. We estimate that the population attributable risk due to this aminoacid substitution for clinically significant disease is about 8% in both populations. Increased conversion of testosterone to dihydrotestosterone catalysed by this variant steroid 5 alpha-reductase enzyme may be the cause of the increased risk.