title: No modification of the beneficial effect of NSAIDs on colorectal cancer by CYP2C9 genotype.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors: Department of Epidemiology and Biostatistics, Erasmus University Medical Centre, Rotterdam, the Netherland.
authors: C
authors: C
authors: Siemes
authors: M
authors: M
authors: Eijgelsheim
authors: J P
authors: JP
authors: Dieleman
authors: R H N
authors: RH
authors: van Schaik
authors: A G
authors: AG
authors: Uitterlinden
authors: C M
authors: CM
authors: van Duijn
authors: A
authors: A
authors: Hofman
authors: J W W
authors: JW
authors: Coebergh
authors: B H Ch
authors: BH
authors: Stricker
authors: L E
authors: LE
authors: Visser
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage* / Q000378:metabolism; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000517:prevention & control*; D065729:Cytochrome P-450 CYP2C9; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009426:Netherlands / Q000453:epidemiology; D016016:Proportional Hazards Models; D011446:Prospective Studies; D012307:Risk Factors
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases