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Pesticide exposure and inherited variants in vitamin d pathway genes in relation to prostate cancer.

ABSTRACT: BACKGROUND:Vitamin D and its metabolites are believed to impede carcinogenesis by stimulating cell differentiation, inhibiting cell proliferation, and inducing apoptosis. Certain pesticides have been shown to deregulate vitamin D's anticarcinogenic properties. We hypothesize that certain pesticides may be linked to prostate cancer via an interaction with vitamin D genetic variants. METHODS:We evaluated interactions between 41 pesticides and 152 single-nucleotide polymorphisms (SNP) in nine vitamin D pathway genes among 776 prostate cancer cases and 1,444 male controls in a nested case-control study of Caucasian pesticide applicators within the Agricultural Health Study. We assessed Pinteraction values using likelihood ratio tests from unconditional logistic regression and a false discovery rate (FDR) to account for multiple comparisons. RESULTS:Five significant interactions (P < 0.01) displayed a monotonic increase in prostate cancer risk with individual pesticide use in one genotype and no association in the other. These interactions involved parathion and terbufos use and three vitamin D genes (VDR, RXRB, and GC). The exposure-response pattern among participants with increasing parathion use with the homozygous CC genotype for GC rs7041 compared with unexposed participants was noteworthy [low vs. no exposure: OR, 2.58, 95% confidence interval (CI), 1.07-6.25; high vs. no exposure: OR, 3.09, 95% CI, 1.10-8.68; Pinteraction = 3.8 × 10(-3)]. CONCLUSIONS:In this study, genetic variations in vitamin D pathway genes, particularly GC rs7041, an SNP previously linked to lower circulating vitamin D levels, modified pesticide associations with prostate cancer risk. IMPACT:Because our study is the first to examine this relationship, additional studies are needed to rule out chance findings.

SUBMITTER: Karami S

PROVIDER: S-EPMC3773544 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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Pesticide exposure and inherited variants in vitamin d pathway genes in relation to prostate cancer.

Karami Sara S Andreotti Gabriella G Koutros Stella S Barry Kathryn Hughes KH Moore Lee E LE Han Summer S Hoppin Jane A JA Sandler Dale P DP Lubin Jay H JH Burdette Laurie A LA Yuenger Jeffrey J Yeager Meredith M Freeman Laura E Beane LE Blair Aaron A Alavanja Michael C R MC

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 20130705 9

<h4>Background</h4>Vitamin D and its metabolites are believed to impede carcinogenesis by stimulating cell differentiation, inhibiting cell proliferation, and inducing apoptosis. Certain pesticides have been shown to deregulate vitamin D's anticarcinogenic properties. We hypothesize that certain pesticides may be linked to prostate cancer via an interaction with vitamin D genetic variants.<h4>Methods</h4>We evaluated interactions between 41 pesticides and 152 single-nucleotide polymorphisms (SNP ...[more]

PMID: 23833127

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Project description:BACKGROUND:Previous research indicates increased prostate cancer risk for pesticide applicators and pesticide manufacturing workers. Although underlying mechanisms are unknown, evidence suggests a role of oxidative DNA damage. OBJECTIVES:Because base excision repair (BER) is the predominant pathway involved in repairing oxidative damage, we evaluated interactions between 39 pesticides and 394 tag single-nucleotide polymorphisms (SNPs) for 31 BER genes among 776 prostate cancer cases and 1,444 male controls in a nested case-control study of white Agricultural Health Study (AHS) pesticide applicators. METHODS:We used likelihood ratio tests from logistic regression models to determine p-values for interactions between three-level pesticide exposure variables (none/low/high) and SNPs (assuming a dominant model), and the false discovery rate (FDR) multiple comparison adjustment approach. RESULTS:The interaction between fonofos and rs1983132 in NEIL3 [nei endonuclease VIII-like 3 (Escherichia coli)], which encodes a glycosylase that can initiate BER, was the most significant overall [interaction p-value (pinteract) = 9.3 × 10-6; FDR-adjusted p-value = 0.01]. Fonofos exposure was associated with a monotonic increase in prostate cancer risk among men with CT/TT genotypes for rs1983132 [odds ratios (95% confidence intervals) for low and high use compared with no use were 1.65 (0.91, 3.01) and 3.25 (1.78, 5.92), respectively], whereas fonofos was not associated with prostate cancer risk among men with the CC genotype. Carbofuran and S-ethyl dipropylthiocarbamate (EPTC) interacted similarly with rs1983132; however, these interactions did not meet an FDR < 0.2. CONCLUSIONS:Our significant finding regarding fonofos is consistent with previous AHS findings of increased prostate cancer risk with fonofos exposure among those with a family history of prostate cancer. Although requiring replication, our findings suggest a role of BER genetic variation in pesticide-associated prostate cancer risk.

Dataset Information

Pesticide exposure and inherited variants in vitamin d pathway genes in relation to prostate cancer.

Publications

Pesticide exposure and inherited variants in vitamin d pathway genes in relation to prostate cancer.

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