R&D, Department of Clinical Chemistry, Ulleval University Hospital, Kirkeveien 166, O407 Oslo, Norway.
Center for Clinical Research, Ulleval University Hospital, Kirkeveien 166, 0407 Oslo, Norway.
Thromb J. 2008 Jun 17;6:7. doi: 10.1186/1477-9560-6-7.
Warfarin treatment has a narrow therapeutic range, requiring meticulous monitoring and dosage titration. Individual dosage requirement has recently partly been explained by genetic variation of the warfarin metabolizing enzyme CYP2C9 and the Vitamin K-activating enzyme VKORC1. In the WARIS-II study, comparing three different antithrombotic regimens after myocardial infarction, warfarin treatment reduced thrombotic events, but was associated with more frequent bleeding than use of acetylsalisylic acid (ASA) alone.
The primary aim of the present study was to investigate the relation between genotypes of CYP2C9 and VKORC1 and warfarin maintenance dose in myocardial infarction. The secondary aim was to relate the genotypes to international normalized ratio (INR).
Genotyping was performed in 212 myocardial infarction patients from the WARIS-II study by robotic isolation of DNA from EDTA whole blood (MagNa Pure LC) before PCR amplification (LightCycler) and melting point analysis.
The 420 C>T substitution of CYP2C92, the 1075 A>C substitution of CYP2C93 and the 1173 C>T substitution of VKORC1 had minor allele frequencies of, 11.3%, 5.7% and 36.6% respectively. Warfarin weekly dose varied between 17 mg and 74 mg among the patients. INR did not vary between genotypes. Warfarin dosage requirement was significantly associated with CYP2C9 and VKORC1 genotypes, treatment group and age. The VKORC1 genotype contributed 24.5% to the interindividual variation in warfarin dosage, whereas the combined CYP2C9 genotypes were only responsible for 7.2% of the dose variation.
CYP2C9 and VKORC1 genotype frequencies in myocardial infarction patients appear similar to other patient groups and have similar impact on warfarin maintenance dose.
华法林治疗的治疗范围较窄，需要精细的监测和剂量滴定。华法林代谢酶 CYP2C9 和维生素 K 激活酶 VKORC1 的遗传变异部分解释了个体剂量需求。在 WARIS-II 研究中，比较心肌梗死后三种不同的抗血栓治疗方案，华法林治疗降低了血栓事件，但与单独使用乙酰水杨酸（ASA）相比，出血更频繁。
本研究的主要目的是研究 CYP2C9 和 VKORC1 基因型与心肌梗死后华法林维持剂量的关系。次要目的是将基因型与国际标准化比值（INR）相关联。
通过从 EDTA 全血（MagNa Pure LC）中机器人分离 DNA（MagNa Pure LC），对来自 WARIS-II 研究的 212 例心肌梗死患者进行 CYP2C9 和 VKORC1 的基因分型，然后进行 PCR 扩增（LightCycler）和熔点分析。
CYP2C92 的 420 C>T 取代、CYP2C93 的 1075 A>C 取代和 VKORC1 的 1173 C>T 取代的次要等位基因频率分别为 11.3%、5.7%和 36.6%。患者的华法林每周剂量在 17 毫克至 74 毫克之间变化。基因型之间的 INR 没有差异。华法林剂量需求与 CYP2C9 和 VKORC1 基因型、治疗组和年龄显著相关。VKORC1 基因型对华法林剂量的个体间变异的贡献为 24.5%，而 CYP2C9 基因型的组合仅对剂量变化的 7.2%负责。
心肌梗死患者的 CYP2C9 和 VKORC1 基因型频率与其他患者群体相似，对华法林维持剂量有相似的影响。
