Effect of VKORC1-1639 G>A polymorphism, body weight, age, and serum albumin alterations on warfarin response in Japanese patients.
BACKGROUND
To establish individualized warfarin therapy, we investigated the contribution of genetic variations of vitamin K epoxide reductase complex subunit 1 gene (VKORC1) -1639 G>A and Cytochrome P450 2C9 gene (CYP2C9) and clinical factors on warfarin sensitivity in Japanese patients.


METHODS
Genetic analyses of VKORC1 -1639 G>A and CYP2C9 2, 3, and 4 were performed in 259 Japanese patients and 341 healthy subjects. We selected 259 patients who have been prescribed warfarin with a 1.5-3.0 range of prothrombin time normalized as an international normalized ratio for at least 3 months and investigated factors that contribute to individual variability in warfarin dose. Furthermore, multivariate analysis was performed to investigate a warfarin dosing algorithm.


CONCLUSIONS
There were great inter-individual differences in warfarin maintenance dose in 259 patients, ranging from a minimum dose of 0.75 mg/day to a maximal dose of 8.00 mg/day. VKORC1 -1639 G>A polymorphism, body weight, age, and serum albumin were found to affect the inter-individual variability. The dosing algorithm of warfarin maintenance dose was investigated by multivariate linear regression. The regression equation was able to account for 33.2% (R(2)(Adj)=0.332) of the overall variability in warfarin dose.
Yoshizawa
Misa
M
Department of Clinical Pharmacology & Genetics, School of Pharmaceutical Sciences, University of Shizuoka, Suruga-ku, Shizuoka, Japan.
Hayashi
Hideki
H
Tashiro
Yoshio
Y
Sakawa
Sonoko
S
Moriwaki
Hideaki
H
Akimoto
Takehide
T
Doi
Osamu
O
Kimura
Midori
M
Kawarasaki
Yoshinori
Y
Inoue
Kazuyuki
K
Itoh
Kunihiko
K
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000465:Algorithms; D000483:Alleles; D000925:Anticoagulants / Q000008:administration & dosage* / Q000627:therapeutic use; D001189:Aryl Hydrocarbon Hydroxylases; D001835:Body Weight / Q000235:genetics*; D065729:Cytochrome P-450 CYP2C9; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D007564:Japan / Q000453:epidemiology; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics*; D011110:Polymorphism, Genetic; D012189:Retrospective Studies; D012709:Serum Albumin / Q000235:genetics*; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000008:administration & dosage* / Q000627:therapeutic use
D000925:Anticoagulants; D012709:Serum Albumin; D014859:Warfarin; 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