Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA.
Mayo Clin Proc. 2009 Dec;84(12):1079-94. doi: 10.4065/mcp.2009.0278.
The antithrombotic benefits of warfarin are countered by a narrow therapeutic index that contributes to excessive bleeding or cerebrovascular clotting and stroke in some patients. This article reviews the current literature describing warfarin sensitivity genotyping and compares the results of that review to the findings of our study in 189 patients at Mayo Clinic conducted between June 2001 and April 2003. For the review of the literature, we identified relevant peer-reviewed articles by searching the Web of Knowledge using key word warfarin-related adverse event. For the 189 Mayo Clinic patients initiating warfarin therapy to achieve a target international normalized ratio (INR) in the range of 2.0 to 3.5, we analyzed the CYP2C9 (cytochrome P450 2C9) and VKORC1 (vitamin K epoxide reductase complex, subunit 1) genetic loci to study the relationship among the initial warfarin dose, steady-state dose, time to achieve steady-state dose, variations in INR, and allelic variance. Results were compared with those previously reported in the literature for 637 patients. The relationships between allelic variants and warfarin sensitivity found in our study of Mayo Clinic patients are fundamentally the same as in those reported by others. The Mayo Clinic population is predominantly white and shows considerable allelic variability in CYP2C9 and VKORC1. Certain of these alleles are associated with increased sensitivity to warfarin. Polymorphisms in CYP2C9 and VKORC1 have a considerable effect on warfarin dose in white people. A correlation between steady-state warfarin dose and allelic variants of CYP2C9 and VKORC1 has been demonstrated by many previous reports and is reconfirmed in this report. The allelic variants found to most affect warfarin sensitivity are CYP2C911-VKORC1BB (less warfarin sensitivity than typical); CYP2C911-VKORC1AA (considerable variance in INR throughout initiation); CYP2C912-VKORC1AB (more sensitivity to warfarin than typical); CYP2C913-VKORC1AB (much more sensitivity to warfarin than typical); CYP2C912-VKORC1AB (much more sensitivity to warfarin than typical); CYP2C913-VKORC1AA (much more sensitivity to warfarin than typical); and CYP2C922-VKORC1AB (much more sensitivity to warfarin than typical). Although we were unable to show an association between allelic variants and initial warfarin dose or dose escalation, an association was seen between allelic variant and steady-state warfarin dose. White people show considerable variance in CYP2C9 allele types, whereas people of Asian or African descent infrequently carry CYP2C9 allelic variants. The VKORC1AA allele associated with high warfarin sensitivity predominates in those of Asian descent, whereas white people and those of African descent show diversity, carrying either the VKORC1BB, an allele associated with low warfarin sensitivity, or VKORC1AB or VKORC1AA, alleles associated with moderate and high warfarin sensitivity, respectively.
华法林的抗血栓形成益处被其狭窄的治疗指数所抵消，这导致一些患者出现过度出血或脑血管血栓形成和中风。本文综述了目前描述华法林敏感性基因分型的文献，并将这些结果与我们在梅奥诊所的 189 名患者的研究结果进行了比较，该研究于 2001 年 6 月至 2003 年 4 月进行。对于文献综述，我们通过在 Web of Knowledge 上使用关键字“华法林相关不良事件”搜索，确定了相关的同行评议文章。对于在梅奥诊所开始华法林治疗以达到国际标准化比值（INR）在 2.0 至 3.5 范围内的 189 名患者，我们分析了 CYP2C9（细胞色素 P450 2C9）和 VKORC1（维生素 K 环氧化物还原酶复合物，亚单位 1）遗传位点，以研究初始华法林剂量、稳态剂量、达到稳态剂量的时间、INR 变化和等位基因变异之间的关系。结果与之前文献中 637 名患者的结果进行了比较。我们在梅奥诊所患者研究中发现的等位基因变异与华法林敏感性之间的关系与其他人报告的基本相同。梅奥诊所的人群主要是白人，并且在 CYP2C9 和 VKORC1 中表现出相当大的等位基因变异。某些等位基因与对华法林的敏感性增加有关。CYP2C9 和 VKORC1 的多态性对白种人华法林剂量有很大影响。许多先前的报告证明了稳定状态华法林剂量与 CYP2C9 和 VKORC1 等位基因变异之间的相关性，并在本报告中再次得到证实。发现最能影响华法林敏感性的等位基因变异是 CYP2C911-VKORC1BB（比典型情况对华法林的敏感性降低）；CYP2C911-VKORC1AA（INR 在整个起始阶段都有很大变化）；CYP2C912-VKORC1AB（对华法林的敏感性比典型情况增加）；CYP2C913-VKORC1AB（比典型情况对华法林的敏感性增加很多）；CYP2C912-VKORC1AB（比典型情况对华法林的敏感性增加很多）；CYP2C913-VKORC1AA（比典型情况对华法林的敏感性增加很多）；和 CYP2C922-VKORC1AB（比典型情况对华法林的敏感性增加很多）。尽管我们无法显示等位基因变异与初始华法林剂量或剂量递增之间的关联，但我们发现等位基因变异与稳定状态华法林剂量之间存在关联。白人在 CYP2C9 等位基因类型上表现出相当大的差异，而亚洲或非洲裔人群很少携带 CYP2C9 等位基因变异。与高华法林敏感性相关的 VKORC1AA 等位基因在亚洲血统中占优势，而白人和非洲裔人群则表现出多样性，携带 VKORC1BB（与低华法林敏感性相关的等位基因）或 VKORC1AB 或 VKORC1AA（分别与中等到高华法林敏感性相关的等位基因）。
