Association of pharmacokinetic (CYP2C9) and pharmacodynamic (factors II, VII, IX, and X; proteins S and C; and gamma-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-->Met of the factor II gene, -402G-->A, (37-bp repeat)n, and -746T-->C of the factor VII gene, and (CAA repeat)n of the gamma-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 were 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.
Shikata
Eriko
E
Department of Hospital Pharmacy, Faculty of Medicine, Tottori University, Yonago, Japan.
Ieiri
Ichiro
I
Ishiguro
Shingo
S
Aono
Hironao
H
Inoue
Kazuko
K
Koide
Tomoko
T
Ohgi
Shigetsugu
S
Otsubo
Kenji
K
D000925:Anticoagulants / Q000494:pharmacology*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D001779:Blood Coagulation Factors / Q000235:genetics*; D065729:Cytochrome P-450 CYP2C9; D005164:Factor IX / Q000235:genetics; D005167:Factor VII / Q000235:genetics; D005170:Factor X / Q000235:genetics; D014644:Genetic Variation; D006801:Humans; D009154:Mutation; D011110:Polymorphism, Genetic; D018807:Polymorphism, Single-Stranded Conformational; D011486:Protein C / Q000235:genetics*; D017293:Protein S / Q000235:genetics*; D011516:Prothrombin / Q000235:genetics*; D014859:Warfarin / Q000494:pharmacology*
D000925:Anticoagulants; D001779:Blood Coagulation Factors; D011486:Protein C; D017293:Protein S; D014859:Warfarin; D005167:Factor VII; D011516:Prothrombin; D005164:Factor IX; D005170:Factor X; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases