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

Abstract

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). 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. 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). 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.