Jiang Hai He, Liu Jia, Wang Yi Chen, Ye Hui Ming, Li Xi, Zhou Ya Xing, Zhang Wei, Wang Lian Sheng
1 Department of Cardiothoracic Surgery, Xiangya Hospital, Central South University, Chang Sha, Hu Na, China.
2 Translational Medicine Center, Zhengzhou Central Hospital, Zhengzhou University, Zhengzhou, Henan Sheng, China.
Clin Appl Thromb Hemost. 2018 May;24(4):640-646. doi: 10.1177/1076029617703483. Epub 2017 Apr 12.
Differences in warfarin maintenance dosages based on the presence of polymorphisms in VKORC1, CYP2C9, CYP4F2, and ORM1 can be determined through dosage adjustment according to routine guidelines. Little is known about whether routine therapy could provide consensus anticoagulation control for patients with different genotypes. This study was carried out to compare anticoagulant control in patients with different genotypes. Six hundred seventy patients using warfarin according to Chinese guidelines were enrolled. Warfarin dosages and monitored international normalized ratios (INRs) were recorded. Genotypes of VKORC1 rs9923231, CYP4F2 rs2108622, CYP2C9 rs1057910, and ORM1 rs17650 polymorphisms were determined. Warfarin dosages and INR were compared between genotypes. Patients with the AGCCFF11 polymorphism took longer than patients with the AACCFF11 polymorphism (20 vs 5 days, P < .001) to achieve the targeted INR range. The INR values of patients with AACCFF13 were unstable and did not enter the stable state control phase until after 35 days. The peak INR of patients with the AACCFF13 polymorphism was exceedingly high, with some values exceeding the control range limit of 3.0. Patients with the AACCFS11 or AACTFF11 polymorphisms exhibited similar INR values as the patients with the AACCFF11 polymorphism. This study found that routine medication with warfarin provides significantly different levels of anticoagulant control between patients with wild-type genotypes and patients with heterozygous polymorphism genotypes of VKORC1 rs9923231 or CYP2C9 rs1057910. Patients with heterozygous polymorphism genotypes of VKORC1 or CYP2C9 require genotype-directed therapy with warfarin to increase efficacy and safety in anticoagulant treatment.
基于维生素K环氧化物还原酶复合体亚单位1（VKORC1）、细胞色素P450 2C9（CYP2C9）、细胞色素P450 4F2（CYP4F2）和ORM1基因多态性存在与否的华法林维持剂量差异，可通过依据常规指南进行剂量调整来确定。对于常规治疗能否为不同基因型患者提供一致的抗凝控制，目前知之甚少。本研究旨在比较不同基因型患者的抗凝控制情况。纳入了670例按照中国指南使用华法林的患者。记录华法林剂量及监测的国际标准化比值（INR）。测定VKORC1 rs9923231、CYP4F2 rs2108622、CYP2C9 rs1057910和ORM1 rs17650基因多态性的基因型。比较不同基因型之间的华法林剂量和INR。具有AGCCFF11基因多态性的患者比具有AACCFF11基因多态性的患者达到目标INR范围所需时间更长（20天对5天，P <.001）。具有AACCFF13基因多态性的患者的INR值不稳定，直到35天后才进入稳定状态控制阶段。具有AACCFF13基因多态性的患者的INR峰值极高，有些值超过了3.0的控制范围上限。具有AACCFS11或AACTFF11基因多态性的患者的INR值与具有AACCFF11基因多态性的患者相似。本研究发现，对于野生型基因型患者以及VKORC1 rs9923231或CYP2C9 rs1057910杂合多态性基因型患者，常规使用华法林进行治疗所提供的抗凝控制水平存在显著差异。具有VKORC1或CYP2C9杂合多态性基因型的患者需要采用华法林基因导向治疗，以提高抗凝治疗的疗效和安全性。
