title: The bleeding risk during warfarin therapy is associated with the number of variant alleles of CYP2C9 and VKORC1 genes.
abstract: BACKGROUND
  Warfarin is commonly used for the treatment and prevention of arterial and venous thromboembolism but its use is hindered by the risk of bleeding. The main reason for this risk is a narrow therapeutic index and a wide response variability after warfarin treatment. These shortcomings affect clinical outcomes including bleeding complications and may be associated with variant polymorphisms in the CYP2C9 and VKORC1 genes.
  
  
  OBJECTIVE
  It was the aim of this study to assess the impact of the total variant allele count of CYP2C9 and VKORC1 genes on bleeding related to warfarin treatment.
  
  
  METHODS
  In a retrospective cohort-design study, patients were genotyped for polymorphisms in genes CYP2C9 (*1, *2, *3) and VKORC1 (haplotype A, B). Extensive clinical data were obtained. Adjusted hazard ratios (HR) for the occurrence of major bleeding events (MBE) were counted separately for the induction and maintenance phases of warfarin therapy.
  
  
  RESULTS
  Out of the 329 patients in our clinical database, 194 patients were eligible and included in the analysis. MBE occurred in 51 patients (26.3%) during a mean follow-up of 26 months: 6 patients (11.8%) experienced early MBE during warfarin initiation, and 45 MBE occurred during the maintenance phase. The adjusted HR for MBE risk for patients with any CYP2C9 variant allele was 1.962 [95% confidence interval (CI) 1.08-3.56, p = 0.027]; for the VKORC1 AA haplotype, HR was 1.841 (95% CI 0.97-3.48, p = 0.06), while for 3 variant allele carriers of both genes, HR was 4.34 (95% CI 1.95-9.65, p < 0.001). Despite the insignificant association of the VKORC1 genotype with bleeding in our study, we have noted a warfarin dose-dependent effect with risk significance ascending: CYP2C9 *1/*1 + VKORC1 B/B < CYP2C9 *1/*1 + VKORC1 A/B < CYP2C9 *1/*2 + VKORC1 B/B.
  
  
  CONCLUSIONS
  Patients who are carriers of 3 variant alleles of the genes CYP2C9 and VKORC1 exhibited a significantly higher risk of MBE during the initiation and maintenance phases of warfarin therapy. Vigilant and careful management of patients with a higher variant allele count, including switching to newer anticoagulants, could be considered in this high-risk cohort.
authors.affiliation: Neurology Department, Charles University, 2nd School of Medicine, Prague, Czech Republic. ales.tomek@fnmotol.cz
authors.forename: Aleš
authors.initials: A
authors.lastname: Tomek
authors.forename: Václav
authors.initials: V
authors.lastname: Maťoška
authors.forename: Tereza
authors.initials: T
authors.lastname: Kolářová
authors.forename: Jiří
authors.initials: J
authors.lastname: Neumann
authors.forename: Martin
authors.initials: M
authors.lastname: Srámek
authors.forename: Ivana
authors.initials: I
authors.lastname: Sarbochová
authors.forename: Luděk
authors.initials: L
authors.lastname: Táborský
authors.forename: Martin
authors.initials: M
authors.lastname: Bojar
authors.forename: Petr
authors.initials: P
authors.lastname: Goetz
authors.forename: Victor L
authors.initials: VL
authors.lastname: Serebruany
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000925:Anticoagulants / Q000009:adverse effects*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D065729:Cytochrome P-450 CYP2C9; D005260:Female; D014644:Genetic Variation; D006470:Hemorrhage / Q000139:chemically induced* / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012307:Risk Factors; D064417:Vitamin K Epoxide Reductases / Q000235:genetics*; D014859:Warfarin / Q000009:adverse effects*
chemical_list: D000925:Anticoagulants; D014859:Warfarin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases