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
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
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DOI：
10.1097/01.fpc.0000184955.08453.a8
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发表时间：
2006-02-01
影响因子：
2.6
通讯作者：
Echizen, Hirotoshi
中科院分区：
文献类型：
--
作者：
Takahashi, Harumi;Wilkinson, Grant R.;Echizen, Hirotoshi
目的探讨与华法林抗凝剂量人群差异相关的药代动力学和药效学因素，特别是维生素K环氧化物还原酶（VKOR）和细胞色素P450 2C 9（CYP 2C 9）基因变异性的可能参与。方法测定157名白人、172名日本人、157名中国人和157名中国人华法林维持剂量、血浆游离S-华法林浓度[ Cu（S）]和国际标准化比值（INR）。和36名稳定抗凝的非裔美国人患者。在一个子集（n=166），完全羧化血浆正常凝血酶原水平（NPT）也进行了测量。在115名白人、64名日本患者和66名健康非裔美国人中进行了7种CYP 2C 9（CYP 2C 9 *1至6和 *11）和7种VKORC 1变体的基因分型。结果NPT与Cu（S）之间的相关性表明日本人比其他两个群体更容易受到S-华法林抑制NPT的产生。VKORC 1 1173 C > T在日本人中的频率（89.1%）高于高加索人（42.2%）和非洲裔美国人（8.6%）。代谢能力降低的CYP 2C 9变异体在日本人群中的频率低于其他两个人群。白人患者的华法林中位剂量显著高于日本患者（5.5 vs 3.5 mg/天），然而，当CYP 2C 9 *1纯合性匹配时，VKORC 1基因型匹配组之间未观察到剂量差异。结论VKORC 1和CYP 2C 9基因多态性对华法林剂量的影响可能存在群体间差异，但对群体内差异的影响可能存在差异。
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.