title: Evaluation of Oxidative Stress Response Related Genetic Variants, Pro-oxidants, Antioxidants and Prostate Cancer.
abstract: BACKGROUND
  Oxidative stress and detoxification mechanisms have been commonly studied in Prostate Cancer (PCa) due to their function in the detoxification of potentially damaging reactive oxygen species (ROS) and carcinogens. However, findings have been either inconsistent or inconclusive. These mixed findings may, in part, relate to failure to consider interactions among oxidative stress response related genetic variants along with pro- and antioxidant factors.
  
  
  METHODS
  We examined the effects of 33 genetic and 26 environmental oxidative stress and defense factors on PCa risk and disease aggressiveness among 2,286 men from the Cancer Genetic Markers of Susceptibility project (1,175 cases, 1,111 controls). Single and joint effects were analyzed using a comprehensive statistical approach involving logistic regression, multi-dimensionality reduction, and entropy graphs.
  
  
  RESULTS
  Inheritance of oneCYP2C8 rs7909236T or twoSOD2 rs2758331A alleles was linked to a 1.3- and 1.4-fold increase in risk of developing PCa, respectively (p-value = 0.006-0.013). Carriers ofCYP1B1 rs1800440GG, CYP2C8 rs1058932TCand,NAT2(rs1208GG, rs1390358CC, rs7832071TT) genotypes were associated with a 1.3 to 2.2-fold increase in aggressive PCa [p-value = 0.04-0.001, FDR 0.088-0.939]. We observed a 23% reduction in aggressive disease linked to inheritance of one or moreNAT2 rs4646247A alleles (p= 0.04, FDR = 0.405). Only threeNAT2sequence variants remained significant after adjusting for multiple hypotheses testing, namelyNAT2 rs1208, rs1390358, andrs7832071. Lastly, there were no significant gene-environment or gene-gene interactions associated with PCa outcomes.
  
  
  CONCLUSIONS
  Variations in genes involved in oxidative stress and defense pathways may modify PCa. Our findings do not firmly support the role of oxidative stress genetic variants combined with lifestyle/environmental factors as modifiers of PCa and disease progression. However, additional multi-center studies poised to pool genetic and environmental data are needed to make strong conclusions.
authors.affiliation: Department of Pharmacology and Toxicology and James Graham Brown Cancer Center, University of Louisville, Louisville, KY.
authors.forename: Nicole
authors.initials: N
authors.lastname: Lavender
authors.affiliation: Department of Pharmacology and Toxicology and James Graham Brown Cancer Center, University of Louisville, Louisville, KY.
authors.forename: David W
authors.initials: DW
authors.lastname: Hein
authors.affiliation: Department of Bioinformatics and Biostatistics, University of Louisville, Louisville, KY.
authors.forename: Guy
authors.initials: G
authors.lastname: Brock
authors.affiliation: Department of Pharmacology and Toxicology and James Graham Brown Cancer Center, University of Louisville, Louisville, KY.
authors.forename: La Creis R
authors.initials: CR
authors.lastname: Kidd
keywords: Cancer Genetics Markers of Susceptibility; Prostate cancer; gene-environment interactions; gene-gene interactions; genome wide association study; multifactor dimensionality reduction; oxidative stress