Meat-related mutagen exposure, xenobiotic metabolizing gene polymorphisms and the risk of advanced colorectal adenoma and cancer

Abstract

Meat mutagens, including heterocyclic amines (HCAs), polycyclic aromatic hydrocarbons (PAHs) and N-nitroso compounds (NOCs), may be involved in colorectal carcinogenesis depending on their activation or detoxification by phase I and II xenobiotic metabolizing enzymes (XME). Using unconditional logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI), we examined the intake of five meat mutagens and >300 single nucleotide polymorphisms (SNPs) in 18 XME genes in relation to advanced colorectal adenoma (1205 cases and 1387 controls) and colorectal cancer (370 cases and 401 controls) within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Dietary intake of meat mutagens was assessed using a food frequency questionnaire with a detailed meat-cooking module. An interaction was observed between 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) intake and the NAT1 polymorphism rs6586714 in the adenoma study (P(interaction) = 0.001). Among individuals carrying a GG genotype, high MeIQx intake was associated with a 43% increased risk of adenoma (95% CI 1.11-1.85, P(trend) = 0.07), whereas the reverse was observed among carriers of the A variant (OR = 0.50, 95% CI 0.30-0.84, P(trend) = 0.01). In addition, we observed some suggestive (P < 0.05) modifying effects for SNPs in other XME genes (UGT1A, CYP2E1, EPHX1, AHR and GSTM3), but these were not significant after adjustment for multiple testing. This large and comprehensive study of XME genes, meat mutagens and the risk of colorectal tumours found that a NAT1 polymorphism modified the association between MeIQx intake and colorectal adenoma risk.

Fig. 1.

Schematic representation of the two-step test for G×E interaction of Murcray et al. (31). We first excluded SNPs with call rate <90%, minor allele frequency (MAF) <1% in the adenoma set and 5% in the cancer set, or Hardy–Weinberg Equilibrium (HWE) P-value <1×10⁻⁶ among Caucasian controls. In Step 1 of the test G×E interaction, G–E association were first tested in the combined case and control sample. Only SNPs with P < 0.10 in Step 1 are then tested for G×E interaction using a standard case–control analysis in Step 2. We further explored the risk pattern for all interactions that met the unadjusted significance threshold of 0.05 (see Tables 3 and 4). *Significant after adjustment for multiple testing at P < 0.05.