title: Effects of CYP4F2 polymorphism on response to warfarin during induction phase: a prospective, open-label, observational cohort study.
abstract: BACKGROUND
  The cytochrome P450 (CYP) 4F2 isozyme has been reported to metabolize vitamin K(1) in vitro, and the V433M polymorphism in the CYP4F2 gene has been associated with reduced vitamin K(1) metabolism and the need for a higher maintenance dosage in patients receiving warfarin.
  
  
  OBJECTIVE
  The purpose of the present study was to evaluate the effects of V433M polymorphism on warfarin response during the induction phase.
  
  
  METHODS
  Warfarin-naive white patients in whom warfarin was scheduled to be initiated with a target INR of 2 to 3 were enrolled into the study. On enrollment, a single blood sample for the genotyping of CYP4F2, CYP2C9, and VKORC1 was drawn. The international normalized ratio (INR) was followed daily during induction and twice weekly until stable anticoagulation was reached. The relationships between several markers of warfarin response during induction and CYP4F2 polymorphism were determined.
  
  
  RESULTS
  The cohort consisted of 241 patients (115 men; mean [SD] age, 55.2 [19.4] years; weight, 79.5 [18.3] kg). Most of the patients were carriers of the CYP4F2 CC genotype (112 patients) or the CT genotype (104 patients). In carriers of the TT genotype (25 patients), INR >3 was >4-fold lower compared with that in carriers of the CC or CT genotype, suggesting that patients with the TT genotype were less sensitive to warfarin during induction. Also in TT carriers, the extent of excessive anticoagulation was >10-fold lower than in the other carriers. Both of these findings had a nominal P value of <0.05. After adjustment for false discovery rate, none of the findings remained significant at a threshold q value of <0.05. Among CC carriers, the concurrent use of a statin was associated with a 1-mg/d reduction in warfarin maintenance dosage. No similar effect was noted in the CT or TT carriers, suggesting a possible genetic influence on warfarin-statin interaction.
  
  
  CONCLUSIONS
  These preliminary findings suggest that among white patients treated with warfarin, CYP4F2 polymorphism had a measurable effect on warfarin responsiveness during induction; however, the observed differences failed to reach the level of statistical significance. The possibility that the effect of statins on warfarin anticoagulation varies among carriers of different CYP4F2 genotypes could not be excluded and should be evaluated further in a larger patient sample.
authors.affiliation: Clinical Pharmacology Unit, Division of Medicine, Hadassah University Hospital, Jerusalem, Israel.
authors.forename: Idit
authors.initials: I
authors.lastname: Bejarano-Achache
authors.forename: Liran
authors.initials: L
authors.lastname: Levy
authors.forename: Liat
authors.initials: L
authors.lastname: Mlynarsky
authors.forename: Meir
authors.initials: M
authors.lastname: Bialer
authors.forename: Mordechai
authors.initials: M
authors.lastname: Muszkat
authors.forename: Yoseph
authors.initials: Y
authors.lastname: Caraco
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants / Q000627:therapeutic use*; D001483:Base Sequence; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D000072470:Cytochrome P450 Family 4; D017931:DNA Primers; D005260:Female; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D014859:Warfarin / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D000925:Anticoagulants; D017931:DNA Primers; D014859:Warfarin; D003577:Cytochrome P-450 Enzyme System; D000072470:Cytochrome P450 Family 4; C117480:CYP4F2 protein, human