Association of pharmacokinetic (CYP2C9) and pharmacodynamic (factors II, VII, IX,andX;proteins SandC; and γ-glutamyl carboxylase) gene variants with warfarin sensitivity

We analyzed mutations of 7 vitamin K—dependent protein and cytochrome P450 2C9 genes in 45 patients and investigated whether any contribute to the large interpatient variability in the warfarin dose-effect relationship. Total clearance and daily dose, INR and INR/Cp, were used as pharmacokinetic and pharmacodynamic indexes, respectively. Patients were grouped by genotype based on a single polymorphism and combinations of polymorphisms. Among the 30 sequence variants identified,CYP2C9*3, 165Thr → Metof thefactor IIgene, -402G → A, (37-bp repeat)n, and -746T → Cof thefactor VIIgene, and(CAA repeat)nof the γ-glutamyl carboxylasegene were selected as candidate polymorphisms. As the analysis of single polymorphisms implied, the highest INR/Cp mean values and the lowest warfarin maintenance doses were observed in patients homozygous for the165Met, -402G, (37-bp repeat)6and -746Talleles. Multiple regression analysis revealed that warfarin sensitivity was independently associated with -402G→A, (CAA repeat)n,CYP2C9*3, and165Thr → Met, which accounted for 50% of variance. These results suggest that part of the considerable interpatient variation is attributable to genetic variation, and the combined genotyping ofCYP2C9and certain vitamin K—dependent protein genes is useful for predicting anticoagulant responses.