Xenobiotic metabolizing gene variants, dietary heterocyclic amine intake, and risk of prostate cancer

We recently reported that heterocyclic amines (HCA) are associated with prostate cancer risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. We now use extensive genetic data from this resource to determine if risks associated with dietary HCAs {2-amino-l-methyi-6-phenyl- imidazo[4,5-¿»]pyridine (PhIP); 2-amino-3,8-dimethylimi-dazo[4,5-6] quinoxaline (MeIQx); and 2-amino-3,4,8-trimethylimidazo[4,5-]quinoxaline (DiMelQx)} from cooked meat are modified by single nucleotide polymorphisms (SNP) in genes involved in HCA metabolism (CYPlAl, CYP1A2, CYPlBl, GSTAl, GSTMl, GSTM3, GSTPl, NATI, NAT2, SUlTlAl, SULT1A2, and UGTlA locus). We conducted a nested case-control study that included 1,126 prostate cancer cases and 1,127 controls selected for a genome-wide association study for prostate cancer. Unconditional logistic regression was used to estimate odds ratios (OR), 95% confidence intervals (95% CI), and P values for the interaction between SNPs, HCA intake, and risk of prostate cancer. The strongest evidence for an interaction was noted between DiMeIQx and MeIQx and the polymorphism rslll02001 downstream of the GSTM3 locus (interaction = 0.001 for both HCAs; statistically significant after correction for multiple testing). Among men carrying the A variant, the risk of prostate cancer associated with high DiMeIQx intake was 2-fold greater than that with low intake (OR, 2.3; 95% CI, 1.2-4.7). The SNP rslll02001, which encodes a nonsynonymous amino acid change P356S in EPS8L3, is a potential candidate modifier of the effect of HCAs on prostate cancer risk. The observed effect provides evidence to support the hypothesis that HCAs may act as promoters of malignant transformation by altering mitogenic signaling.