Takahashi Harumi, Ieiri Ichiro, Wilkinson Grant R, Mayo Gail, Kashima Toshitaka, Kimura Sosuke, Otsubo Kenji, Echizen Hirotoshi
Department of Pharmacotherapy, Meiji Pharmaceutical University, Kiyose, Tokyo, Japan.
Blood. 2004 Apr 15;103(8):3055-7. doi: 10.1182/blood-2003-07-2521. Epub 2003 Dec 30.
White and Japanese patients require different warfarin dosages to achieve therapeutic anticoagulation, but this can be only partly explained by genetic variability in the coding region of CYP2C9-a critical enzyme in the drug's metabolism. Accordingly, analysis of the -2.1-kb 5'-flanking region of CYP2C9 was undertaken in 22 white and 38 Japanese patients whose unbound oral clearance of S-warfarin had been previously determined. Thirteen single nucleotide polymorphisms (SNPs) were identified, some of which were in linkage disequilibrium with functionally defective coding region variants. Those 5'-flanking patterns linked with at least one CYP2C93 allele or CYP2C92/*3 were associated with reduced CYP2C9 activity and warfarin dose. Japanese patients possessing the wild-type promoter and coding sequences had significantly (P <.01) greater CYP2C9 activity than white patients with the corresponding genotype. In conclusion, either unidentified polymorphisms further upstream in the promoter region or environmental factor(s) account for the differences in the warfarin doses between whites and Japanese.
白种人和日本患者需要不同剂量的华法林来实现治疗性抗凝，但这只能部分归因于CYP2C9编码区的基因变异，CYP2C9是该药物代谢中的关键酶。因此，对22名白种人和38名日本患者进行了CYP2C9基因-2.1 kb 5'侧翼区分析，这些患者之前已测定了S-华法林的非结合口服清除率。共鉴定出13个单核苷酸多态性（SNP），其中一些与功能缺陷的编码区变异处于连锁不平衡状态。那些与至少一个CYP2C93等位基因或CYP2C92/*3相关的5'侧翼模式与CYP2C9活性降低和华法林剂量减少有关。具有野生型启动子和编码序列的日本患者的CYP2C9活性显著（P<.01）高于具有相应基因型的白种人患者。总之，启动子区域上游未识别的多态性或环境因素导致了白种人和日本患者华法林剂量的差异。
