Microsomal epoxide hydrolase polymorphisms and risk for advanced colorectal adenoma

Cigarette smoking is a risk factor for colorectal adenoma, a precursor of colorectal cancer. Microsomal epoxide hydrolase (EPHX1) metabolizes polycyclic aromatic hydrocarbons, carcinogens found in cigarette smoke. Nonsynonymous variants of EPHX1 at Tyr ₁₁₃His (exon 3) and His ₁₃₉Arg (exon 4) are associated, respectively, with low ( ₁₁₃His) and high ( ₁₃₉Arg) predicted activity. Among participants randomized to the screening arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, we evaluated risks for advanced adenoma in relation to cigarette use and these two EPHX1 variants. We compared 772 cases with advanced adenoma (adenoma ≥1 cm or containing high-grade dysplasia or villous, including tubulovillous, elements) of the distal colon (left-sided, descending colon and sigmoid or rectum) to 777 gender- and age-matched controls who were screennegative for left-sided adenoma. Compared to those with homozygous genotypes predicting low EPHX1 activity, advanced adenoma risks tended to be elevated for carriers of ₁₁₃TyrTyr [odds ratios (OR), 1.5; 95% confidence intervals (CI), 1.0-2.2] and ₁₃₉ArgArg (OR, 1.4; 95% CI, 0.8-2.5) and for subjects who carried a greater number of the alleles ( ₁₁₃Tyr or ₁₃₉Arg) associated with high predicted enzymatic activity (P _trend = 0.03). The increased risk associated with the increasing number of putative high-activity alleles was most apparent among current and recent (quit <10 years) cigarette smokers (P _trend = 0.02). In conclusion, EPHX1 variants at codon 113 and 139 associated with high predicted enzymatic activity appear to increase risk for colorectal adenoma, particularly among recent and current smokers.