Iron overload may increase
prostate cancer risk through stimulation of oxidative stress, and endogenous pro- and
antioxidant capabilities, i.e.
manganese superoxide dismutase (MnSOD) and
myeloperoxidase (MPO), may modify these associations. We investigated this hypothesis in the
Carotene and
Retinol Efficacy Trial cohort in a nested case-control study. Although there was no association between
iron intake and risk overall, there was a suggestion of increased risk of clinically aggressive
prostate cancer with higher
iron intake [odds ratio (OR) = 1.4, 95% confidence interval (CI) = 0.9-2.0]. Associations were most notable for men with aggressive
prostate cancer who were below the median consumption of total fruits and vegetables (OR = 1.8, 95% CI = 1.1-3.2). Associations between MPO -463 G to A genotype (rs2333227) and
prostate cancer risk were only noted among men with aggressive
cancer, with more than a 2-fold risk reduction among men with AA genotypes (OR = 0.4, 95% CI = 0.2-1.0); MnSOD was not associated with risk overall, but the MnSOD T to C (Val-9Ala, rs4880) polymorphism modified associations between risk of clinically aggressive
prostate cancer and
dietary iron intake (P for interaction = 0.02). Among aggressive
cancer cases with the TT genotype, higher
iron intake level was associated with >2-fold increase in risk (OR = 2.3, 95% CI = 1.0-4.9), whereas there was no association among men with CC genotypes (OR = 0.9, 95% CI = 0.4-2.3). Although interactions were not significant, there were similar patterns for MPO genotype,
iron intake and risk. These findings suggest that higher
iron intake may be associated with risk of clinically aggressive
prostate cancer, and that
endogenous antioxidant capabilities may modify these associations.