title: Role of NQO1C609T and EPHX1 gene polymorphisms in the association of smoking and alcohol with sporadic distal colorectal adenomas: results from the UKFSS Study.
abstract: 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 between NQO1C609T, mEH3, mEH4 and 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. The NQO1 609*T allele 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 by NQO1C609T genotype, such that the relation between alcohol and colorectal adenoma was stronger among those with the common C/C genotype (OR, 1.49; 95% CI, 1.11-2.02; P-interaction = 0.024). There was no association between mEH3 and mEH4 variants and colorectal adenoma risk and no effect modification by alcohol and smoking. These findings provide evidence for an important role of the NQO1C609T polymorphism 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.
authors.affiliation: Dunn Human Nutrition Unit, MRC/Wellcome Trust Building, Hills Road, Cambridge CB2 2XY, UK.
authors.forename: Panagiota N
authors.initials: PN
authors.lastname: Mitrou
authors.forename: Mark A
authors.initials: MA
authors.lastname: Watson
authors.forename: Alexandre S
authors.initials: AS
authors.lastname: Loktionov
authors.forename: Christopher
authors.initials: C
authors.lastname: Cardwell
authors.forename: Marc J
authors.initials: MJ
authors.lastname: Gunter
authors.forename: Wendy S
authors.initials: WS
authors.lastname: Atkin
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Macklin
authors.forename: Tom
authors.initials: T
authors.lastname: Cecil
authors.forename: D Timothy
authors.initials: DT
authors.lastname: Bishop
authors.forename: John
authors.initials: J
authors.lastname: Primrose
authors.forename: Sheila A
authors.initials: SA
authors.lastname: Bingham
mesh_terms: D000236:Adenoma / Q000235:genetics* / Q000473:pathology; D000368:Aged; D000428:Alcohol Drinking; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D004032:Diet; D004851:Epoxide Hydrolases / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008403:Mass Screening; D008875:Middle Aged; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics*; D016017:Odds Ratio; D011110:Polymorphism, Genetic; D012307:Risk Factors; D012907:Smoking
chemical_list: D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; D004851:Epoxide Hydrolases