Background: CYP2C9 enzymes are involved in non-steroidal anti-inflammatory drug (NSAID) metabolism. Therefore, we investigated whether CYP2C9*2 and *3 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 CYP2C9*2 and 3 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 CYP2C9 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 CYP2C9*2 and/or *3 carriage are associated with a reduced risk of colorectal cancer. However, no interaction between the determinants was found, which might indicate independent pathophysiological mechanisms.

Anti-inflammatory agents, Caucasian, Cohort studies, Colorectal neoplasms, Cytochrome p-450 enzyme system, Interaction non-steroid, Polymorphism, Single nucleotide, acetylsalicylic acid, adult, aged, article, azapropazone, cancer incidence, cancer risk, carbasalate calcium, celecoxib, cohort analysis, colorectal cancer, cytochrome P450 2C9, dexketoprofen, diclofenac, dietary intake, diflunisal, drug use, enzyme activity, etoricoxib, female, flurbiprofen, gene frequency, genetic association, genetic variability, genotype, heterozygote, human, ibuprofen, indometacin, ketoprofen, major clinical study, male, meloxicam, misoprostol, nabumetone, naproxen, nonsteroid antiinflammatory agent, piroxicam, population research, rectum cancer, risk reduction, rofecoxib, sigmoid, sigmoid cancer, sulindac, tolmetin
hdl.handle.net/1765/16442
The Netherlands Journal of Medicine
Erasmus MC: University Medical Center Rotterdam

Siemes, C, Eijgelsheim, M, Dieleman, J.P, van Schaik, R.H.N, Uitterlinden, A.G, van Duijn, C.M, … Visser, L.E. (2009). No modification of the beneficial effect of NSAIDs on colorectal cancer by CYP2C9 genotype. The Netherlands Journal of Medicine, 2009(4), 134–141. Retrieved from http://hdl.handle.net/1765/16442