The Influence of CYP2C9 and VKORC1 Gene Polymorphisms on Optimal Warfarin Doses After Heart Valve Replacement

UNLABELLED: 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. MATERIALS AND 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.