title: CYP2C9 variants as a risk modifier of NSAID-related gastrointestinal bleeding: a case-control study.
abstract: OBJECTIVE
  The aim of this study was to assess whether the CYP2C9*2 and/or *3 variants might modify the risk for NSAID-related upper gastrointestinal bleeding (UGIB) in NSAID users.
  
  
  METHODS
  We conducted a multicenter, case-control study in which cases were patients aged more than 18 years with a diagnosis of UGIB, and controls were matched (1 : 3) by sex, age, date of admission, and hospital. Exposure was defined as the mean number of defined daily doses (DDDs) of NSAIDs metabolized by CYP2C9 in the week preceding the index date. Three DDD categories were defined (0, ≤ 0.5, and > 0.5). Exposure was constructed taking both NSAID use and CYP2C9 polymorphisms into account. Patients of non-European origin were excluded from the analysis.
  
  
  RESULTS
  A total of 577 cases and 1343 controls were finally included in the analysis: 103 cases and 89 controls consumed NSAIDs metabolized by CYP2C9, and 88 cases and 177 controls were CYP2C9*3 carriers. The adjusted odds ratios (aORs) of UGIB associated with the CYP2C9*2 and wild-type alleles proved to be similar [OR=8.79 (4.50-17.17) and 10.15 (2.92-35.35), respectively] and lower than those of the CYP2C9*3 allele [aOR=18.07 (6.34-51.53)] for consumers taking more than 0.5 DDDs of NSAIDs metabolized by CYP2C9. Grouping genotypes into carriers and noncarriers of the CYP2C9*3 variant resulted in aORs of 16.92 (4.96-57.59) for carriers and 9.72 (4.55-20.76) for noncarriers, where DDDs were greater than 0.5.
  
  
  CONCLUSIONS
  The presence of the CYP2C9*3 variant increases the risk for UGIB associated with NSAID for DDDs greater than 0.5. The presence of the CYP2C9*2 allele shows no such effect.
authors.affiliation: aDepartment of Preventive Medicine and Public Health, Santiago de Compostela University, Santiago de Compostela bBiomedical Research Network Consortium of Epidemiology and Public Health (CIBER en Epidemiología y Salud Pública - CIBERESP) cBasque Country Pharmacovigilance Unit, Galdakao-Usansolo Hospital, Galdakao dDepartment of Pharmacology, Basque Country University School of Medicine, Leioa, Basque Country eDepartment of Pharmacology, Therapeutics and Toxicology, Autonomous University, Catalonian Institute of Pharmacology, Clinical Pharmacology Service, Vall d'Hebron University Hospital, Barcelona fPharmacoepidemiology Institute, University of Valladolid, Valladolid, Spain gService of Digestive Endoscopy hClinical Pharmacology Unit, Verona University Hospital, Verona, Italy.
authors.forename: Adolfo
authors.initials: A
authors.lastname: Figueiras
authors.forename: Ana
authors.initials: A
authors.lastname: Estany-Gestal
authors.forename: Carmelo
authors.initials: C
authors.lastname: Aguirre
authors.forename: Borja
authors.initials: B
authors.lastname: Ruiz
authors.forename: Xavier
authors.initials: X
authors.lastname: Vidal
authors.forename: Alfonso
authors.initials: A
authors.lastname: Carvajal
authors.forename: Inés
authors.initials: I
authors.lastname: Salado
authors.forename: Angel
authors.initials: A
authors.lastname: Salgado-Barreira
authors.forename: Luca
authors.initials: L
authors.lastname: Rodella
authors.forename: Ugo
authors.initials: U
authors.lastname: Moretti
authors.forename: Luisa
authors.initials: L
authors.lastname: Ibáñez
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects*; D016022:Case-Control Studies; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics*; D005260:Female; D006471:Gastrointestinal Hemorrhage / Q000139:chemically induced* / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9