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NADP(H):quinone oxidoreductase 1 (NQO1) and microsomal epoxide hydrolase (EPHX1, also mEH) are attractive candidate enzymes for association with colorectal neoplasia because they metabolize a number of compounds including polycyclic aromatic hydrocarbons (PAHs) that have been linked with colorectal carcinogenesis. We examined the relationship betweenNQO1C609T,mEH3,mEH4and risk of sporadic distal colorectal adenomas in one of the largest case–control studies of 946 polyp-free controls and 894 cases, all participants of the UK Flexible Sigmoidoscopy Screening (UKFSS) Trial. The polymorphisms were examined as independent risk factors and evidence for interaction with smoking and alcoholic drinks was sought. TheNQO1609*  Tallele was positively associated with high-risk adenoma in this population [odds ratio (OR), 1.36; 95% confidence interval (CI), 1.02–1.83]. Elevated risk estimates were seen in smokers independently of the genotype but the association was stronger among current smokers with the heterozygous variant genotype (OR, 4.24; 95% CI, 2.54–7.09). It was reported for the first time that the association between alcohol and colorectal adenoma was modified byNQO1C609Tgenotype, such that the relation between alcohol and colorectal adenoma was stronger among those with the commonC/Cgenotype (OR, 1.49; 95% CI, 1.11–2.02;P-interaction = 0.024). There was no association betweenmEH3andmEH4variants and colorectal adenoma risk and no effect modification by alcohol and smoking. These findings provide evidence for an important role of theNQO1C609Tpolymorphism in susceptibility of colorectal adenomas. Alcohol increases risk of colorectal adenoma in carriers of the high-activity genotype possibly through enhanced activation of alcohol-related procarcinogens.

carcinogenesis

Role of               NQO1C609T               and               EPHX1               gene polymorphisms in the association of smoking and alcohol with sporadic distal colorectal adenomas: results from the UKFSS Study