BACKGROUND:Low levels of selenium have been associated with increased risk of prostate cancer (PCa). Selenoprotein P is the most abundant selenoprotein in serum and delivers ten selenocysteine residues to tissues. Variation in the selenoprotein P gene (SEPP1) may influence PCa development or modify the effects of selenium. We examined the association of SEPP1 single nucleotide polymorphisms (SNPs) with PCa risk and survival, and tested for interactions. METHODS:The Physicians' Health Study (PHS) is a prospective cohort of 22,071 US physicians; we utilized a nested case-control study of 1,352 PCa cases and 1,382 controls. We assessed four SNPs capturing common variation within the SEPP1 locus. In a subset of men (n = 80), we evaluated SEPP1 mRNA expression in tumors. RESULTS:Two SNPs were significantly associated with PCa risk. For rs11959466, each T allele increased risk (odds ratio (OR) = 1.31; 95% confidence interval (CI): 1.02,1.69; P(trend)  = 0.03). For rs13168440, the rare homozygote genotype decreased risk compared to the common homozygote (OR = 0.56, 95% CI: 0.33, 0.96). Moreover, there was a significant interaction of rs13168440 with plasma selenium; increasing selenium levels were associated with decreased PCa risk only among men with the minor allele (P(interaction)  = 0.01). SEPP1 expression was significantly lower in men with lethal PCa than long-term survivors. CONCLUSIONS:SEPP1 genetic variation was associated with PCa incidence; replication of these results in an independent dataset is necessary. These findings further support a causal link between selenium and PCa, and suggest that the effect of selenium may differ by genetics.

译文

背景:硒水平过低与前列腺癌(PCa)的风险增加有关。硒蛋白P是血清中含量最丰富的硒蛋白,可向组织输送十个硒代半胱氨酸残基。硒蛋白P基因(SEPP1)的变异可能会影响PCa的发育或改变硒的作用。我们检查了SEPP1单核苷酸多态性(SNP)与PCa风险和生存的关联,并测试了相互作用。
方法:《医师健康研究》(PHS)是美国22,071名医师的前瞻性队列研究。我们利用了对1352个PCa病例和1382个对照的嵌套病例对照研究。我们评估了四个捕获SEPP1基因座内常见变异的SNP。在一组男性患者中(n = 80),我们评估了SEPP1 mRNA在肿瘤中的表达。
结果:两个SNP与PCa风险显着相关。对于rs11959466,每个T等位基因的患病风险增加(几率(OR)= 1.31; 95%置信区间(CI):1.02,1.69; P(趋势)= 0.03)。对于rs13168440,与普通纯合子相比,罕见的纯合子基因型降低了风险(OR = 0.56,95%CI:0.33,0.96)。此外,rs13168440与血浆硒之间存在显着的相互作用。硒水平升高与等位基因较小的男性中PCa风险降低相关(P(相互作用)= 0.01)。具有致死性PCa的男性SEPP1表达明显低于长期存活者。
结论:SEPP1基因变异与PCa发生率有关。必须将这些结果复制到独立的数据集中。这些发现进一步支持了硒与PCa之间的因果关系,并表明硒的作用可能因遗传因素而有所不同。

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