title: Clinical Practice Recommendations on Genetic Testing of CYP2C9 and VKORC1 Variants in Warfarin Therapy.
abstract: OBJECTIVE
  To systematically review evidence on genetic variants influencing outcomes during warfarin therapy and provide practice recommendations addressing the key questions: (1) Should genetic testing be performed in patients with an indication for warfarin therapy to improve achievement of stable anticoagulation and reduce adverse effects? (2) Are there subgroups of patients who may benefit more from genetic testing compared with others? (3) How should patients with an indication for warfarin therapy be managed based on their genetic test results?
  
  
  METHODS
  A systematic literature search was performed for VKORC1 and CYP2C9 and their association with warfarin therapy. Evidence was critically appraised, and clinical practice recommendations were developed based on expert group consensus.
  
  
  RESULTS
  Testing of VKORC1 (-1639G>A), CYP2C9*2, and CYP2C9*3 should be considered for all patients, including pediatric patients, within the first 2 weeks of therapy or after a bleeding event. Testing for CYP2C9*5, *6, *8, or *11 and CYP4F2 (V433M) is currently not recommended. Testing should also be considered for all patients who are at increased risk of bleeding complications, who consistently show out-of-range international normalized ratios, or suffer adverse events while receiving warfarin. Genotyping results should be interpreted using a pharmacogenetic dosing algorithm to estimate the required dose.
  
  
  CONCLUSIONS
  This review provides the latest update on genetic markers for warfarin therapy, clinical practice recommendations as a basis for informed decision making regarding the use of genotype-guided dosing in patients with an indication for warfarin therapy, and identifies knowledge gaps to guide future research.
authors.affiliation: *Division of Translational Therapeutics, Department of Pediatrics, University of British Columbia; †Pharmaceutical Outcomes Programme, British Columbia Children's Hospital; ‡Child and Family Research Institute, Vancouver, British Columbia, Canada; §Institute of Clinical Chemistry, Inselspital Bern University Hospital, University of Bern, Switzerland; ¶Division of Clinical Pharmacology, Department of Medicine, Western University, London, Ontario, Canada; ‖Department of Pharmaceutics, University of Florida, Orlando; **CRCHUM, Centre Hospitalier de l'Université de Montréal and Faculty of Pharmacy, Université de Montréal, Québec; ††Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver; and ‡‡Division of Clinical Pharmacology and Toxicology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Ontario, Canada.
authors.forename: Kaitlyn
authors.initials: K
authors.lastname: Shaw
authors.forename: Ursula
authors.initials: U
authors.lastname: Amstutz
authors.forename: Richard B
authors.initials: RB
authors.lastname: Kim
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Lesko
authors.forename: Jacques
authors.initials: J
authors.lastname: Turgeon
authors.forename: Veronique
authors.initials: V
authors.lastname: Michaud
authors.forename: Soomi
authors.initials: S
authors.lastname: Hwang
authors.forename: Shinya
authors.initials: S
authors.lastname: Ito
authors.forename: Colin
authors.initials: C
authors.lastname: Ross
authors.forename: Bruce C
authors.initials: BC
authors.lastname: Carleton
mesh_terms: D000925:Anticoagulants / Q000009:adverse effects / Q000627:therapeutic use; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics*; D005820:Genetic Testing; D006801:Humans; D017410:Practice Guidelines as Topic; D064417:Vitamin K Epoxide Reductases / Q000235:genetics*; D014859:Warfarin / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D000925:Anticoagulants; D014859:Warfarin; D065729:Cytochrome P-450 CYP2C9; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases