Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA.
Prostate. 2013 May;73(7):700-5. doi: 10.1002/pros.22611. Epub 2012 Nov 5.
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.
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.
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.
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.
低水平的硒与前列腺癌（PCa）风险增加有关。硒蛋白 P 是血清中含量最丰富的硒蛋白，可将十个硒代半胱氨酸残基递送至组织。硒蛋白 P 基因（SEPP1）的变异可能会影响 PCa 的发展或改变硒的作用。我们研究了 SEPP1 单核苷酸多态性（SNP）与 PCa 风险和生存的关联，并检测了相互作用。
医师健康研究（PHS）是一项由 22071 名美国医师组成的前瞻性队列研究；我们利用了一项包含 1352 例 PCa 病例和 1382 例对照的嵌套病例对照研究。我们评估了 SEPP1 基因座内常见变异的四个 SNP。在一部分男性（n=80）中，我们评估了肿瘤中的 SEPP1 mRNA 表达。
有两个 SNP 与 PCa 风险显著相关。对于 rs11959466，每个 T 等位基因都会增加风险（比值比（OR）=1.31；95%置信区间（CI）：1.02,1.69；P 趋势=0.03）。对于 rs13168440，罕见的纯合基因型与常见的纯合基因型相比，风险降低（OR=0.56，95%CI：0.33,0.96）。此外，rs13168440 与血浆硒之间存在显著的相互作用；只有携带次要等位基因的男性中，随着硒水平的升高，PCa 风险降低（P 相互作用=0.01）。与长期幸存者相比，致命性 PCa 男性的 SEPP1 表达明显降低。
SEPP1 遗传变异与 PCa 发病率有关；在独立数据集上复制这些结果是必要的。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而异。
