Background: CYP2C9 enzymes are involved in
non-steroidal anti-inf lammatory drug (NSAID) metabolism. Therefore, we investigated whether <i>CYP2C9*2</i> and <i>*3</i> variant alleles, encoding for enzymes with lower activity, increased the protective effect of NSAIDs on colorectal cancer.
Methods: Individual and combined associations of NSAIDs and <i>CYP2C9*2</i> and <i>*3</i> variant alleles with colorectal cancer were studied in 7757 Caucasian individuals of The Rotterdam Study, a population-based prospective cohort since 1990. Additive and multiplicative effect modification models were used to examine drug-gene interactions.
Results: There were 212 incident cases of colorectal cancer during follow-up. A reduced risk of colorectal cancer was observed in individuals who used NSAIDs for more than a year (HR 0.45; 95% CI 0.28 to 0.71), and in carriers of an <i>CYP2C9</i> variant allele associated with lower enzymatic activity (HR 0.67; 95% CI 0.47 to 0.96). The combination of both determinants was associated with a further risk reduction but without synergy.
Conclusion: Both NSAID use and <i>CYP2C9*2</i> and/
or <i>*3</i> carriage are associated with a reduced risk of colorectal cancer. However, no interaction between the determinants was found, which might indicate independent pathophysiological