Abstract
Background: Selenoprotein P (SelP) is the most common selenoprotein in serum and delivers selenium around the body, carrying up to ten selenocysteine residues per polypeptide. Antioxidants such as selenium may decrease the risk of developing prostate cancer (PCa). One study observed that serum SelP levels were lower in PCa cases than in controls while another found the expression of the gene, SEPP1, decreased with progression from normal prostate tissue to carcinoma to metastatic disease. Genetic variation in SEPP1 may also influence PCa risk or progression, or may modify the effects of selenium. We examined the association of single nucleotide polymorphisms (SNPs) in SEPP1 with PCa risk and survival, and tested for interactions with plasma selenium levels.
Methods: The Physicians' Health Study (PHS) is a prospective cohort of 22,071 US physicians, of whom 2,584 were diagnosed with PCa between 1982 and 2005. Blood was collected from 68% of participants at baseline. We used a nested case‐control study of 1,352 PCa cases and 1,382 controls matched on age, smoking status, and follow‐up time; analyses were restricted to Caucasians. Using the HapMap database, we selected 5 SNPs to capture variation with a minor allele frequency >5% within SEPP1 and 5 kb up‐ and downstream. Four SNPs had high genotyping success (92–97%); the other failed genotyping, however, it tagged only itself so did not reduce the coverage. The incidence analysis used unconditional logistic regression, adjusting for matching factors. For survival analysis, individuals were censored at death or the end of follow‐up; PCa deaths or metastases were considered lethal events (n=191). Plasma selenium levels were measured on 805 cases and 549 controls.
Results: Two of the four SNPs were significantly associated with risk of incident PCa. For rs11959466, each additional T allele significantly increased the risk of PCa (odds ratio (OR)=1.31; 95% confidence interval (CI): 1.02, 1.69; ptrend=0.03), while for rs13168440, the minor allele homozygote genotype (CC) was associated with a decreased risk compared to the homozygote TT referent (OR=0.56, 95% CI: 0.33, 0.96). Moreover, there was a significant interaction of rs13168440 with quartiles of plasma selenium; increasing levels were associated with a decreased risk of PCa only among men with the minor allele (OR=0.76; 95% CI: 0.62, 0.93; pinteraction=0.02). None of the four SNPs was associated with PCa survival among the cases.
Conclusions: Genetic variation within SEPP1 was associated with PCa incidence and may modify the association of selenium. Considering the multiple hypotheses tested, replication of these findings in an independent data set is needed to confirm or refute these results.
Citation Information: Cancer Prev Res 2010;3(1 Suppl):A122.
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