Influence of clinical and genetic factors on warfarin dose requirements among Japanese patients.
OBJECTIVE
The aim of this study was to investigate the influence of clinical and genetic factors on warfarin dose requirements in the Japanese population.


METHODS
We enrolled 125 patients on stable warfarin anticoagulant therapy with an international normalized ratio maintained between 1.5 and 3.0. PCR-based methods were performed to analyze genetic polymorphisms in the genes pharmacokinetically and pharmacodynamically related to warfarin reactions, including cytochrome P450 (CYP) 2C9, vitamin K epoxide reductase complex subunit 1 (VKORC1), gamma-glutamyl carboxylase (GGCX) and factor VII (FVII).


RESULTS
The presence of CYP2C9*3 and VKORC1-1639G>A had a significant impact on the mean maintenance dose of warfarin (CYP2C9*1/*1 2.74 +/- 1.24 mg/day vs. *1/*3 and *3/*3 1.56 +/- 0.85 mg/day, P = 0.009; VKORC1-1639AA 2.42 +/- 0.95 mg/day vs. GA 3.71 +/- 1.43 mg/day vs. GG 7.25 +/- 0.35 mg/day, P < 0.001). In the multiple linear regression model, the combination of age, body surface area, and genotypes of CYP2C9*3 and VKORC1-1639G>A explained 54.8% of the variance in warfarin dose requirements.


CONCLUSIONS
The influences of CYP2C9*3 and VKORC1-1639G>A on the maintenance dose of warfarin were well-defined in Japanese patients, while polymorphisms of GGCX and FVII did not affect it. The model established in this study might provide us most likely individual maintenance dose based on clinical and genetic backgrounds.
Ohno
Masako
M
Clinical Pharmacology and Pharmacogenomics, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka, 565-0871, Japan.
Yamamoto
Akiko
A
Ono
Ayumu
A
Miura
Genta
G
Funamoto
Masanobu
M
Takemoto
Yasuhiko
Y
Otsu
Kinya
K
Kouno
Yasushi
Y
Tanabe
Tomoko
T
Masunaga
Yuiko
Y
Nonen
Shinpei
S
Fujio
Yasushi
Y
Azuma
Junichi
J
D000368:Aged; D000925:Anticoagulants / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D019735:Carbon-Carbon Ligases / Q000235:genetics; D065729:Cytochrome P-450 CYP2C9; D005167:Factor VII / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D008658:Inactivation, Metabolic / Q000235:genetics*; D007564:Japan; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic / Q000235:genetics*; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000008:administration & dosage* / Q000493:pharmacokinetics
D000925:Anticoagulants; D014859:Warfarin; D005167:Factor VII; 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; D019735:Carbon-Carbon Ligases; C020660:glutamyl carboxylase