title: Cytochrome P450 2C9 variants influence response to celecoxib for prevention of colorectal adenoma.
abstract: OBJECTIVE
  Variants in the cytochrome P450 2C9 (CYP2C9) gene are associated with impaired metabolism of celecoxib. We examined the influence of CYP2C9*2 (R144C) and CYP2C9*3 (I359L) variants on dose-related response or toxicity in a randomized trial of celecoxib.
  
  
  METHODS
  We identified individuals with CYP2C9*2 and CYP2C9*3 genotypes (>or=1 variant allele) in the Adenoma Prevention with Celecoxib trial. Following adenoma removal, patients were assigned randomly to groups given placebo or low-dose (200 mg twice daily) or high-dose (400 mg twice daily) celecoxib and underwent follow-up colonoscopies at 1 and/or 3 years.
  
  
  RESULTS
  Among 1660 patients, 21% were CYP2C9*2, and 12% were CYP2C9*3 genotypes. Overall, celecoxib was associated with a dose-dependent reduction in adenoma, compared with placebo, with relative risks (RR) of 0.65 (95% confidence interval [CI]: 0.56-0.76) for the low-dose and 0.54 (95% CI: 0.46-0.63) for the high-dose groups. However, the additional protective effect of the high dose, compared with the low-dose, was observed only in those with CYP2C9*3 genotypes (RR, 0.51; 95% CI: 0.30-0.87). The high dose, compared with low dose, was not associated with significant risk reduction among those with CYP2C9*2 (RR, 0.83; 95% CI: 0.57-1.21) or wild-type (RR, 0.89; 95% CI: 0.72-1.11) genotypes. Compared with placebo, a higher incidence of cardiovascular events was associated with both doses among patients with wild-type genotypes but only with the high dose among patients with variant genotypes.
  
  
  CONCLUSIONS
  The greater efficacy of high-dose celecoxib, compared with the low-dose, in preventing colorectal adenoma appears confined to individuals with slow metabolizer (CYP2C9*3) genotypes. Genetic variability influences susceptibility to the potential benefits and hazards of celecoxib.
authors.affiliation: Gastrointestinal Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA. achan@partners.org
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Chan
authors.forename: Ann G
authors.initials: AG
authors.lastname: Zauber
authors.forename: Meier
authors.initials: M
authors.lastname: Hsu
authors.forename: Aurora
authors.initials: A
authors.lastname: Breazna
authors.forename: David J
authors.initials: DJ
authors.lastname: Hunter
authors.forename: Rebecca B
authors.initials: RB
authors.lastname: Rosenstein
authors.forename: Craig J
authors.initials: CJ
authors.lastname: Eagle
authors.forename: Ernest T
authors.initials: ET
authors.lastname: Hawk
authors.forename: Monica M
authors.initials: MM
authors.lastname: Bertagnolli
mesh_terms: D000236:Adenoma / Q000188:drug therapy* / Q000235:genetics* / Q000517:prevention & control; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001189:Aryl Hydrocarbon Hydroxylases / Q000187:drug effects / Q000235:genetics*; D000068579:Celecoxib; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000517:prevention & control; D016001:Confidence Intervals; D065729:Cytochrome P-450 CYP2C9; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D011336:Probability; D011720:Pyrazoles / Q000627:therapeutic use*; D012016:Reference Values; D018570:Risk Assessment; D012680:Sensitivity and Specificity; D013449:Sulfonamides / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D011720:Pyrazoles; D013449:Sulfonamides; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D000068579:Celecoxib