title: Genetic variation in base excision repair pathway genes, pesticide exposure, and prostate cancer risk.
abstract: 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.
  
  
  OBJECTIVE
  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.
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Rockville, Maryland 20892-7240, USA. barrykh@mail.nih.gov
authors.forename: Kathryn Hughes
authors.initials: KH
authors.lastname: Barry
authors.forename: Stella
authors.initials: S
authors.lastname: Koutros
authors.forename: Sonja I
authors.initials: SI
authors.lastname: Berndt
authors.forename: Gabriella
authors.initials: G
authors.lastname: Andreotti
authors.forename: Jane A
authors.initials: JA
authors.lastname: Hoppin
authors.forename: Dale P
authors.initials: DP
authors.lastname: Sandler
authors.forename: Laurie A
authors.initials: LA
authors.lastname: Burdette
authors.forename: Meredith
authors.initials: M
authors.lastname: Yeager
authors.forename: Laura E Beane
authors.initials: LE
authors.lastname: Freeman
authors.forename: Jay H
authors.initials: JH
authors.lastname: Lubin
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Ma
authors.forename: Tongzhang
authors.initials: T
authors.lastname: Zheng
authors.forename: Michael C R
authors.initials: MC
authors.lastname: Alavanja
mesh_terms: D016022:Case-Control Studies; D004260:DNA Repair / Q000235:genetics*; D004397:Fonofos / Q000009:adverse effects*; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D016013:Likelihood Functions; D016015:Logistic Models; D008297:Male; D009699:N-Glycosyl Hydrolases / Q000235:genetics; D009657:North Carolina / Q000453:epidemiology; D016273:Occupational Exposure / Q000009:adverse effects*; D016017:Odds Ratio; D010575:Pesticides / Q000009:adverse effects*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011471:Prostatic Neoplasms / Q000139:chemically induced* / Q000453:epidemiology* / Q000235:genetics; D018570:Risk Assessment
chemical_list: D010575:Pesticides; D009699:N-Glycosyl Hydrolases; C468764:NEIL3 protein, human; D004397:Fonofos