Different contributions of polymorphisms in VKORC1 and CYP2C9 to intra- and inter-population differences in maintenance dose of warfarin in Japanese, Caucasians and African-Americans.
OBJECTIVE
To investigate pharmacokinetic and pharmacodynamic factors associated with population differences in warfarin doses needed to achieve anticoagulation, in particular the possible involvement of genetic variability in vitamin K epoxide reductase (VKOR) and CYP2C9.


METHODS
Warfarin maintenance dose, unbound plasma S-warfarin concentration [Cu(S)] and INR were determined in 157 Caucasians, 172 Japanese, and 36 African-Americans stably anticoagulated patients. In a subset (n = 166), fully carboxylated plasma normal prothrombin levels (NPT) were also measured. Genotyping for seven CYP2C9 (CYP2C9*1 through 6 and *11) and seven VKORC1 variants were performed in 115 Caucasians and 64 Japanese patients and 66 healthy African-Americans. Multivariate analysis was performed to identify covariates associated with warfarin requirement.


RESULTS
The relationship between NPT and Cu(S) indicated Japanese are more susceptible to inhibition of NPT production by S-warfarin than the other two populations. VKORC1 1173 C > T had a greater frequency in Japanese (89.1%) than Caucasians (42.2%) and African-Americans (8.6%). CYP2C9 variants with reduced metabolizing ability were less frequent in Japanese compared to the other two populations. The median warfarin dose was significantly higher in Caucasians than Japanese patients (5.5 versus 3.5 mg/day), however, when matched for CYP2C9*1 homozygosity, no difference in dose was observed between VKORC1 genotype-matched groups. Furthermore, VKORC1 1173C > T and CYP2C9 (*2/*3/*11) genotypes, age and weight were identified as independent covariates contributing to interpatient variability in warfarin dosage.


CONCLUSIONS
Both VKORC1 and CYP2C9 polymorphisms contribute to inter-population difference in warfarin doses among the three populations, but their contribution to intra-population variability may differ within each population.
Takahashi
Harumi
H
Department of Pharmacotherapy, Meiji Pharmaceutical University, Kiyose, Tokyo, Japan. harumit@my-pharm.ac.jp
Wilkinson
Grant R
GR
Nutescu
Edith A
EA
Morita
Takashi
T
Ritchie
Marylyn D
MD
Scordo
Maria G
MG
Pengo
Vittorio
V
Barban
Martina
M
Padrini
Roberto
R
Ieiri
Ichiro
I
Otsubo
Kenji
K
Kashima
Toshitaka
T
Kimura
Sosuke
S
Kijima
Shinichi
S
Echizen
Hirotoshi
H
D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D044466:Asian People; D044383:Black People; D065729:Cytochrome P-450 CYP2C9; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007223:Infant; D007564:Japan; D008297:Male; D006899:Mixed Function Oxygenases / Q000235:genetics*; D010597:Pharmacogenetics / Q000379:methods*; D014481:United States; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000494:pharmacology*; D044465:White People; D001741:Black or African American
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