title: CYP2C9 gene variants, drug dose, and bleeding risk in warfarin-treated patients: a HuGEnet systematic review and meta-analysis.
abstract: OBJECTIVE
  Two common variant alleles of the cytochrome CYP2C9 (CYP2C9*2 and CYP2C9*3) lead to reduced warfarin metabolism in vitro and in vivo. The study objective was to examine the strength and quality of existing evidence about CYP2C9 gene variants and clinical outcomes in warfarin-treated patients.
  
  
  METHODS
  The study was a systematic review and meta-analysis. Multiple electronic databases were searched, references identified from bibliographies were sought, and experts and authors of primary studies were also contacted. Strict review inclusion criteria were determined. Three reviewers independently extracted data using prepiloted proformas.
  
  
  RESULTS
  In all, 11 studies meeting review inclusion criteria were identified (3029 patients). Nine were included in the meta-analyses (2775 patients). Random effects meta-analyses were performed; statistical heterogeneity and inconsistency was assessed. Twenty percent of patients studied carry a variant allele: CYP2C9*2 12.2% (9.7%-15.0%) and CYP2C9*3, 7.9% (6.5%-9.7%). Mean difference in daily warfarin dose: for CYP2C9*2, the reduction was 0.85 mg (0.60-1.11 mg), a 17% reduction. For CYP2C9*3, the reduction was 1.92 mg (1.37-2.47 mg), a 37% reduction. For CYP2C9*2 or *3, the reduction was 1.47 mg (1.24-1.71 mg), a 27% reduction. The relative bleeding risk for CYP2C9*2 was 1.91 (1.16-3.17) and for CYP2C9*3 1.77 (1.07-2.91). For either variant, the relative risk was 2.26 (1.36-3.75).
  
  
  CONCLUSIONS
  Patients with CYP2C9*2 and CYP2C9*3 alleles have lower mean daily warfarin doses and a greater risk of bleeding. Testing for gene variants could potentially alter clinical management in patients commencing warfarin. Evidence for the clinical utility and cost-effectiveness of genotyping is needed before routine testing can be recommended.
authors.affiliation: Department of Public Health and Primary Care, University of Cambridge and Cambridge Genetics Knowledge Park, Cambridge, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Sanderson
authors.forename: Jon
authors.initials: J
authors.lastname: Emery
authors.forename: Julian
authors.initials: J
authors.lastname: Higgins
mesh_terms: D000483:Alleles; D000925:Anticoagulants / Q000009:adverse effects* / Q000378:metabolism* / Q000627:therapeutic use; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D065729:Cytochrome P-450 CYP2C9; D016208:Databases, Factual; D014644:Genetic Variation; D005838:Genotype; D006470:Hemorrhage / Q000139:chemically induced* / Q000235:genetics*; D006801:Humans; D010597:Pharmacogenetics; D012307:Risk Factors; D016896:Treatment Outcome; D014859:Warfarin / Q000009:adverse effects* / Q000378:metabolism* / Q000627:therapeutic use
chemical_list: D000925:Anticoagulants; D014859:Warfarin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases