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CYP2C9 variants increase risk of colorectal adenoma recurrence and modify associations with smoking but not aspirin treatment

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Abstract

Purpose

The cytochrome P450 2C9 enzyme (CYP2C9) is involved in metabolism of endogenous compounds, drugs, and procarcinogens. Two common nonsynonymous polymorphisms in CYP2C9 are associated with reduced enzyme activity: CYP2C9*2 (rs1799853, R144C) and CYP2C9*3 (rs1057910, I359L).

Methods

We investigated whether CYP2C9 genotype was associated with risk of colorectal adenoma and/or modified associations with aspirin treatment or cigarette smoking in a cohort of 928 participants in a randomized trial of aspirin chemoprevention. Generalized linear regression was used to compute relative risks (RRs) and 95 % confidence intervals (95 % CIs). Multiplicative interactions terms were used to assess effect modification.

Results

CYP2C9 genotype was associated with increased risks for adenoma recurrence of 29 % (RR = 1.29, 95 % CI 1.09–1.51) for ≥1 variant allele (CYP2C9*2 or *3) and 47 % (RR = 1.47, 95 % CI 1.19–1.83) for ≥1 CYP2C9*3 allele. The risk for advanced lesions or multiple (≥3) adenomas was increased by 64 % (RR = 1.64, 95 % CI 1.18–2.28) for ≥1 variant allele (CYP2C9*2 or *3) and 79 % (RR = 1.79, 95 % CI 1.16–2.75) for ≥1 CYP2C9*3 allele. Genotype modified associations with smoking, but not aspirin treatment. The adenoma risk was increased by 26 % (RR = 1.26, 95 % CI 0.99–1.58) for former smokers and 60 % (RR = 1.60, 95 % CI 1.19–2.15) for current smokers among wild-type individuals, but there was no increased risk among individuals with ≥1 variant allele (CYP2C9*2 or *3) (p interaction = 0.04).

Conclusions

Carriers of CYP2C9 variants with lower enzyme activity have increased overall risk of colorectal adenoma but reduced adenoma risk associated with cigarette smoking. These results may be due to effects on the synthesis of endogenous eicosanoids and/or reduced activation of procarcinogens in smoke by CYP2C9 variants.

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Acknowledgments

The authors are grateful to the co-investigators, study coordinators, and participants in the Aspirin/Folate Polyp Prevention Study who made this research possible and to Bayer for providing the aspirin and placebo tablets for the clinical trial. This work was supported by grants from the National Institutes of Health, National Cancer Institute: R01 CA59005 to JA Baron; R03 CA136026 to CM Ulrich.

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Authors and Affiliations

  1. Geisel School of Medicine at Dartmouth, Lebanon, NH, USA

    Elizabeth L. Barry, John A. Baron & Leila A. Mott

  2. Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    Elizabeth M. Poole, Karen W. Makar & Cornelia M. Ulrich

  3. Channing Laboratory, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

    Elizabeth M. Poole

  4. University of North Carolina, Chapel Hill, NC, USA

    John A. Baron & Robert S. Sandler

  5. Denver Department of Veterans Affairs Medical Center, Denver, CO, USA

    Dennis J. Ahnen

  6. University of Colorado School of Medicine, Denver, CO, USA

    Dennis J. Ahnen

  7. Department of Gastroenterology, Hepatology, and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Robert S. Bresalier

  8. Department of Public Health Sciences and Nutritional Sciences, University of Toronto, Toronto, ON, Canada

    Gail E. McKeown-Eyssen

  9. National Center for Tumor Diseases and German Cancer Research Center, Heidelberg, Germany

    Cornelia M. Ulrich

  10. Department of Community and Family Medicine, Geisel School of Medicine at Dartmouth, 46 Centerra Parkway, Suite 300, Lebanon, NH, 03766, USA

    Elizabeth L. Barry

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  1. Elizabeth L. Barry
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  2. Elizabeth M. Poole
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Correspondence to Elizabeth L. Barry.

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Barry, E.L., Poole, E.M., Baron, J.A. et al. CYP2C9 variants increase risk of colorectal adenoma recurrence and modify associations with smoking but not aspirin treatment. Cancer Causes Control 24, 47–54 (2013). https://doi.org/10.1007/s10552-012-0088-6

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  • DOI: https://doi.org/10.1007/s10552-012-0088-6

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