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A large prospective study of SEP15 genetic variation, interaction with plasma selenium levels, and prostate cancer risk and survival.

ABSTRACT: The role of selenium in prostate cancer (PCa) risk remains controversial, but many epidemiologic studies suggest an inverse association with more aggressive disease. A recently discovered selenoprotein, SEP15, which is highly expressed in the prostate, may play a role either independently or by modifying the effects of selenium. We genotyped four common single-nucleotide polymorphisms capturing common variation (frequency >5%; R(2) > 0.8) within SEP15, as well as rs5859 in the 3' untranslated region, previously reported to reduce the efficiency of selenium incorporation into SEP15. We examined the association of these single-nucleotide polymorphisms with PCa risk and PCa-specific mortality, as well as their interactions with plasma selenium levels, in the Physicians' Health Study. In this nested case-control study (1,286 cases and 1,267 controls), SEP15 polymorphisms were not significantly associated with PCa risk. However, among the cases, three variants were significantly associated with PCa-specific mortality [rs479341 hazard ratio (HR), 1.94; 95% confidence interval (95% CI), 1.15-3.25; rs1407131 HR, 2.85; 95% CI, 1.45-5.59; rs561104 HR, 1.54; 95% CI, 1.12-2.11] with a recessive model. Additionally, rs561104 significantly modified the association of plasma selenium with PCa survival (P(interaction) = 0.02); an inverse relationship of high levels of selenium with PCa mortality was apparent only among those without the increased risk genotype. This study provides evidence that SEP15 genetic variation may influence PCa mortality. Additionally, the association of selenium with PCa mortality was modified by a variant, suggesting the possibility that some men with PCa may benefit more from selenium than others, depending on their genotype.

SUBMITTER: Penney KL

PROVIDER: S-EPMC2865569 | biostudies-literature | 2010 May

REPOSITORIES: biostudies-literature

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A large prospective study of SEP15 genetic variation, interaction with plasma selenium levels, and prostate cancer risk and survival.

Penney Kathryn L KL Schumacher Fredrick R FR Li Haojie H Kraft Peter P Morris J Steven JS Kurth Tobias T Mucci Lorelei A LA Hunter David J DJ Kantoff Philip W PW Stampfer Meir J MJ Ma Jing J

Cancer prevention research (Philadelphia, Pa.) 20100427 5

The role of selenium in prostate cancer (PCa) risk remains controversial, but many epidemiologic studies suggest an inverse association with more aggressive disease. A recently discovered selenoprotein, SEP15, which is highly expressed in the prostate, may play a role either independently or by modifying the effects of selenium. We genotyped four common single-nucleotide polymorphisms capturing common variation (frequency >5%; R(2) > 0.8) within SEP15, as well as rs5859 in the 3' untranslated re ...[more]

PMID: 20424130

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Project description:BackgroundGenetic variations in some of the selenoprotein genes, alone or together with an individual's selenium status, may influence risk or progression of prostate cancer. We investigated the impact of genetic variants of selenoproteins on plasma selenium levels and cancer aggressiveness at diagnosis in men with localized prostate cancer (PCa).MethodsThe study cohort comprised 722 patients seen at Dana-Farber Cancer Institute who had localized/locally advanced PCa (i.e., stage T3 or less, N0, and M0) from 1994 to 2001. Fifty-five tagging single nucleotide polymorphisms (SNPs) from six selenoprotein genes (TXNRD1, TXNRD2, SEP15, GPX3, SELENBP1, and SEPP1) were analyzed. Logistic regression is used to examine associations of genotypes and plasma selenium levels with risk of aggressive disease, defined as D'Amico intermediate/high risk categories. Step down permutation was applied to adjust for multiple comparisons.ResultsThree hundred and forty-eight patients (48%) had aggressive disease at diagnosis. Two SNPs were associated with cancer aggressiveness at diagnosis (unadjusted P = 0.017 and 0.018, respectively). The odds ratio for aggressive disease in patients carrying TXNRD2 rs1005873-AG/GG genotypes or SELENBP1 rs10788804-AG/AA genotypes was 1.54 (95% CI = 1.08, 2.20) and 1.45 (95% CI = 1.07, 1.98), respectively, compared to TXNRD2 rs1005873-AA or SELENBP1 rs10788804-GG carriers. Four SNPs in TXNRD2 (rs1005873, rs13054371, rs3788310, and rs9606174) and the rs230820 in SEPP1 were associated with plasma selenium levels (unadjusted P < 0.05). Permutation adjusted P-values were not statistically significant for all these comparisons at the cut-off point of 0.05.ConclusionWe identified polymorphisms in selenoproteins that may influence the plasma selenium levels and may be associated with the risk of presenting with aggressive PCa in men with localized or locally advanced PCa. These results should be validated in other independent datasets.

Project description:Interventions: Participants will take 6 brazil nuts a day for four weeks. This four week intervention will be preceded by a 4 week run-in / wash out phase participants will be advised to exclude any selenium rich foods or green tea during the study This Pilot study will confirm the amount of Brazil Nuts we will use in the study comparing with green tea. This follow up study (Effects of combining Selenium (Se) and green tea on biomarkers for colorectal cancer prevention in human subjects). will be registered with ANZCTR in the near future’ At the initial interview dietary advice will be given. This will give an understanding of the nature of the volunteers diet and the likely influence of Se to the diet and suitability to become involved in the study (if intolerant to nuts volunteers will not participate in the study) We will ask participants not to consume, whenever possible, throughout the study:- Any selenium supplement Any selenium enriched foods, such as nuts, sea food (such as tuna or octopus) The Brazil nut is a large nut that comes from the castanheiro de para tree in Brazil’s rainforests. Each serving of about six to eight nuts contains 4 g of protein and 7 grams each of monosaturated and polysaturated fat. Brazil nuts (Berholletia excelas, family Lecythidaceae) are the richest known food source of selenium, with mean concentrations reported in the literature between 8-83 micrograms Se/g 6 Brazil nuts daily provides 48 micrograms Se/day - 53 micrograms Se/day Primary outcome(s): If supplementation of 6 Brazil nuts/day increases plasma Selenium (Se) levels A blood sample (5mls of whole blood taken on 2 occasions) will be collected at baseline and after intervention, testing for plasma Selenium levels[Blood samples collected at commencement of intervention (week 0) and at end of intervention (wk 4)] Study Design: Purpose: Prevention; Allocation: Non-randomised trial; Masking: Open (masking not used);Assignment: Single group;Type of endpoint: Safety

Dataset Information

A large prospective study of SEP15 genetic variation, interaction with plasma selenium levels, and prostate cancer risk and survival.

Publications

A large prospective study of SEP15 genetic variation, interaction with plasma selenium levels, and prostate cancer risk and survival.

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