title: Pharmacodynamic resistance to warfarin is associated with nucleotide substitutions in VKORC1.
abstract: BACKGROUND
  Vitamin K epoxide reductase subunit 1 (VKORC1) is the molecular target of coumarin anticoagulants and mutations in VKORC1 have been identified previously in individuals who required high warfarin doses.
  
  
  OBJECTIVE
  Detailed characterization of the relationship between variation in VKORC1 and the warfarin resistance phenotype.
  
  
  METHODS
  Serum warfarin concentration and coagulation parameters were determined in 289 subjects who required warfarin doses >20 mg day(-1). The VKORC1 sequence was studied in selected study subjects.
  
  
  RESULTS
  Twenty-eight out of 289 (10%) subjects had serum warfarin >2.3 mg L(-1) during stable therapeutic anticoagulation indicating pharmacodynamic warfarin resistance. Detailed analysis of 15 subjects from this group showed that eight out of 15 (53%) had nucleotide substitutions in VKORC1 predictive of p.V66M, p.L128R, p.V54L or p.D36Y. VKORC1 was normal in the remaining seven out of 15 (47%) subjects and in nine out of nine (100%) subjects with high warfarin dose requirement not caused by pharmacodynamic resistance. At referral, subjects with VKORC1 mutations received a median warfarin dose of 32 mg day(-1) (range 22-55) and had a median serum warfarin concentration of 4.6 mg L(-1) (range 2.6-9.0). VKORC1 substitutions were associated with a requirement for high warfarin doses but not with adverse clinical events. Family members with VKORC1 nucleotide substitutions and not receiving warfarin had undetectable PIVKA-II and K(1) epoxide (K(1)O).
  
  
  CONCLUSIONS
  Nucleotide variations in VKORC1 are a common cause of pharmacodynamic warfarin resistance but are not associated with adverse outcome during anticoagulation. Mutations associated with warfarin resistance do not cause a discernible defect in VKORC1 reductase function.
authors.affiliation: The Centre for Thrombosis and Haemostasis (Nutristasis Unit), Guy's and St Thomas' NHS Foundation Trust, London, UK.
authors.forename: D J
authors.initials: DJ
authors.lastname: Harrington
authors.forename: R
authors.initials: R
authors.lastname: Gorska
authors.forename: R
authors.initials: R
authors.lastname: Wheeler
authors.forename: S
authors.initials: S
authors.lastname: Davidson
authors.forename: S
authors.initials: S
authors.lastname: Murden
authors.forename: C
authors.initials: C
authors.lastname: Morse
authors.forename: M J
authors.initials: MJ
authors.lastname: Shearer
authors.forename: A D
authors.initials: AD
authors.lastname: Mumford
mesh_terms: D015415:Biomarkers / Q000097:blood; D004252:DNA Mutational Analysis; D004351:Drug Resistance; D006801:Humans; D006899:Mixed Function Oxygenases / Q000235:genetics*; D010088:Oxidoreductases; D010599:Pharmacokinetics; D020641:Polymorphism, Single Nucleotide; D011498:Protein Precursors / Q000097:blood; D011516:Prothrombin; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D015415:Biomarkers; D011498:Protein Precursors; C008208:acarboxyprothrombin; D014859:Warfarin; D011516:Prothrombin; D006899:Mixed Function Oxygenases; D010088:Oxidoreductases; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases