Association of pharmacokinetic (CY72C9) and pharmacodynamic (factors II, VII, IX, and X; proteins S and C; 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 ccntribute 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 → Met of the factor II gene, -402G → A (37-bp and repeat)_n, and -746T → C of the factor VII gene, and (CAA repeat)_n of the γ-glutamyl carboxylase gene were selected as candidate polymorphisms. As the analysis of single polymorphisms implied, the highest INR/Cp mean values and the lowest warfarin maintenance doses ware observed in patients homozygous for the 165Met, -402G, (37-bp repeat)₆ and -746T alleles. Multiple regression analysis revealed that warfarin sensitivity was independently associated with -402G → A, (CAA repeat)_n, CYP2C9*3, and 165Thr → 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 of CYP2C9 and certain vitamin K-dependent protein genes is useful for predicting anticoagulant responses.