title: The influence of CYP2C9 and VKORC1 gene polymorphisms on optimal warfarin doses after heart valve replacement.
abstract: A clinical effect of warfarin depends on highly polymorphic drug-metabolizing (CYP2C9) and drug-target (VKORC1) enzymes. The objective of this study was to investigate the impact of CYP2C9*2, CYP2C9*3, and VKORC1 (G-1639A) polymorphisms on the variability of warfarin dosage requirements in Lithuanian patients after heart valve replacement.
  
  
  METHODS
  The study included 83 patients with a mean age of 65.2 years (SD, 13.31) after heart valve replacement with an achieved stable international normalized ratio of 2-3.5. The restriction fragment length polymorphism method was used to identify polymorphisms of VKORC1 and CYP2C9.
  
  
  RESULTS
  Daily warfarin dosage significantly correlated with weight (r=0.4087) and height (r=0.3883) of the patients. Patients younger than 60 years required significantly higher daily warfarin dosages than older patients. Two-thirds (66.3%) of the patients had the wild-type (WT) CYP2C9*1/*1 genotype; 38.6% and 54.2% of the patients had WT VKORC1 (G/G) and VKORC1 (G/A) genotypes, respectively. WT CYP2C9*1/*1 genotype was associated with a higher daily warfarin dosage (5.84 mg [SD, 2.84]) as compared to other CYP2C9 genotypes. Carriers of WT VKORC1 (G/G) required a higher warfarin dose as compared to (A/A) carriers (6.20±2.78 mg and 3.75±1.40 mg, respectively; P=0.04). Patients having CYP2C9*1/*1 or 1/*2 in combination with VKORC1 (G/G) or (G/A) genotypes required the highest daily warfarin dosage in comparison to other combinations of genotypes.
  
  
  CONCLUSIONS
  The Lithuanian study sample is characterized by high a frequency (92.8%) of VKORC1 G/G and G/A genotypes that determines a higher warfarin-loading dose. Analysis of combined CYP2C9 and VKORC1 gene variants allows the prediction of warfarin dosage. These results can be used to individualize treatment with warfarin in the field of heart surgery in Lithuania.
authors.affiliation: Institute of Cardiology, Me-dical Academy, Lithuanian University of Health Sciences, Suki-lėlių 17, 50161 Kaunas, Lithuania. vacis_tatarunas@takas.lt
authors.forename: Vacis
authors.initials: V
authors.lastname: Tatarūnas
authors.forename: Vaiva
authors.initials: V
authors.lastname: Lesauskaitė
authors.forename: Audronė
authors.initials: A
authors.lastname: Veikutienė
authors.forename: Povilas
authors.initials: P
authors.lastname: Jakuška
authors.forename: Rimantas
authors.initials: R
authors.lastname: Benetis
mesh_terms: D000368:Aged; D000925:Anticoagulants / Q000008:administration & dosage*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D065729:Cytochrome P-450 CYP2C9; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance / Q000235:genetics*; D019918:Heart Valve Prosthesis Implantation; D006801:Humans; D008097:Lithuania; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics*; D011110:Polymorphism, Genetic; D012150:Polymorphism, Restriction Fragment Length; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000008:administration & dosage*
chemical_list: D000925:Anticoagulants; D014859:Warfarin; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases