Polymorphisms in xenobiotic metabolizing enzymes and diet influence colorectal adenoma risk

Emma L. Northwood, Faye Elliott, David Forman, Jennifer H. Barrett, Murray J. V. Wilkie, Francis A. Carey, Robert J. C. Steele, Roland Wolf, Timothy Bishop, Gillian Smith

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    Abstract

    Objectives We have earlier shown that diet and xenobiotic metabolizing enzyme genotypes influence colorectal cancer risk, and now investigate whether similar associations are seen in patients with premalignant colorectal adenomas (CRA), recruited during the pilot phase of the Scottish Bowel Screening Programme.

    Methods Nineteen polymorphisms in 13 genes [cytochrome P450 (P450), glutathione S-transferase (GST), N-acetyl transferase, quinone reductase (NQ01) and microsomal epoxide hydrolase (EPHX1) genes] were genotyped using multiplex PCR or Taqman-based allelic discrimination assays and analyzed in conjunction with diet, assessed by food frequency questionnaire, in a case-control study [317 CRA cases (308 cases genotyped), 296 controls]. Findings significant at a nominal 5% level are reported.

    Results CRA risk was inversely associated with fruit (P = 0.02, test for trend) and vegetable (P = 0.001, test for trend) consumption. P450 CYP2C9*3 heterozygotes had reduced CRA risk compared with homozygotes for the reference allele [odds ratio (OR): 0.60; 95% confidence interval (CI): 0.36-0.99], whereas CYP2D6*4 homozygotes (OR: 2.72; 95% CI: 1.18-6.27) and GSTM1 'null' individuals (OR: 1.43; 95% CI: 1.04-1.98) were at increased risk. The protective effect of fruit consumption was confined to GSTP1 (Ala(114)Val) reference allele homozygotes (OR: 0.49; 95% CI: 0.34-0.71, P = 0.03 for interaction). CRA risk was not associated with meat consumption, although a significant interaction between red meat consumption and EPHX1 (His(139)Arg) genotype was noted ( P = 0.02 for interaction).

    Conclusion We report the novel associations between P450 genotype and CRA risk, and highlight the risk association with GSTM1 genotype, common to our CRA and cancer case-control series. In addition, we report a novel modifying influence of GSTP1 genotype on dietary chemoprevention. These novel findings require independent confirmation. Pharmacogenetics and Genomics 20: 315-326 (c) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.

    Original languageEnglish
    Pages (from-to)315-326
    Number of pages12
    JournalPharmacogenetics and Genomics
    Volume20
    Issue number5
    DOIs
    Publication statusPublished - 2010

    Keywords

    • Colorectal adenoma
    • Diet
    • Gene-environment interactions
    • Pharmacogenetics
    • Polymorphism
    • Xenobiotic metabolizing enzymes
    • Glutathione-S-transferase
    • Epoxide hydrolase polymorphisms
    • Cytochrome P450 2D6 CYP2D6
    • Meat consumption
    • Colon cancer
    • Cigarette smoking
    • Genetic polymorphisms
    • Vegetable consumption
    • Heterocyclic amines
    • GSTM1 genotypes

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