Murata Mitsuru
Department of Laboratory Medicine, School of Medicine, Keio University, Shinjuku-ku, Tokyo 160-8582, Japan.
Rinsho Byori. 2011 Jun;59(6):594-7.
Vitamin K-dependent gamma-carboxylation system is crucial to generate active coagulation factors. It consists of gamma-Glutamylcarboxylase (GGCX) and vitamin K-epoxide reductase (VKOR). Warfarin is an anticoagulant that blocks VKOR. Recent studies have shown that genetic variations in a subunit of VKOR complex, VKORC1, and in cytochrome P 450 (CYP) 2C9 genes are strong determinants of individuals' warfarin sensitivity. Algorithms have been proposed to predict warfarin doses, and about 55% of the variance in warfarin dose could be attributed to variations in the VKORC1 and CYP2C9 genes together with age, sex, body-surface area, and presence or absence of heart valve replacement. Contributions of polymorphisms in VKORC1 and CYP2C9 to inter-individual differences of warfarin dose, however, are different among races. Studies have shown that potential clinical and economic benefits of CYP2C9/VKORC1 genotype-guided dosing are only marginal. Thus, evidence is still limited and application of warfarin pharmacogenomics to clinical practice at present needs careful consideration.
维生素K依赖的γ-羧化系统对于生成活性凝血因子至关重要。它由γ-谷氨酰羧化酶（GGCX）和维生素K环氧化物还原酶（VKOR）组成。华法林是一种阻断VKOR的抗凝剂。最近的研究表明，VKOR复合物的一个亚基VKORC1以及细胞色素P 450（CYP）2C9基因的遗传变异是个体对华法林敏感性的重要决定因素。已经提出了预测华法林剂量的算法，华法林剂量约55%的变异可归因于VKORC1和CYP2C9基因的变异，以及年龄、性别、体表面积和是否存在心脏瓣膜置换。然而，VKORC1和CYP2C9基因多态性对华法林剂量个体差异的贡献在不同种族之间有所不同。研究表明，CYP2C9/VKORC1基因型指导给药的潜在临床和经济效益微乎其微。因此，证据仍然有限，目前将华法林药物基因组学应用于临床实践需要谨慎考虑。
