Bedewy Ahmed M L, Sheweita Salah A, Mostafa Mostafa Hasan, Kandil Lamia Saeed
1Hematology Department, Medical Research Institute, Alexandria University, Alexandria, Egypt.
Abraj Al-Shaker, Zaky Ragab Street, Smouha, Alexandria, 21615 Egypt.
Indian J Hematol Blood Transfus. 2018 Apr;34(2):328-336. doi: 10.1007/s12288-016-0725-4. Epub 2016 Sep 27.
Warfarin is the most commonly used drug for chronic prevention of thromboembolic events, it also ranks high among drugs that cause serious adverse events. The variability in dose requirements has been attributed to inter-individual differences in medical, personal, and genetic factor. Cytochrome P-450 2C9 is the principle enzyme that terminates the anticoagulant effect of warfarin by catalyzing the conversion of the pharmacologically more potent S-enantiomer to its inactive metabolites. Warfarin exerts its effect by inhibition of vitamin K epoxide reductase. This protein is encoded by vitamin K epoxide reductase complex subunit 1 gene (VKORC1). The current study aimed to investigate the pharmacogenetic effect of CYP2C9 and VKORC1 gene polymorphisms on the patients response to warfarin. One hundred cases starting warfarin treatment and 20 healthy controls were enrolled. The mean daily dose of warfarin was calculated from patient's medical records. For each patient, less than 10 % variability in warfarin dose and a target international normalized ratio (INR) within the therapeutic target range were required for at least 3 months for one of the following indications (deep vein thrombosis, pulmonary embolism, cerebrovascular stroke and myocardial infarction) prior to inclusion in the study. Tetraprimer amplification refractory mutation system PCR was performed to determine CYP2C92, CYP2C93, and the VKORC1 1639 G > A genetic polymorphisms. Plasma warfarin determination was performed using rapid fluorometric assay. Plasma warfarin concentration ranged from 2.19 to 10.98 μg/ml with a median 3.52 μg/ml. Supratherpeutic INR was observed in 11 % of the cases. Thromboembolic complications occurred in 7 % of the cases and 8 % of cases experienced major bleeding. High maintenance dose (>7 mg/day) was associated with the combined non VKORC12 and homozygous wild type CYP2C9 (CYP2C91*1) alleles, while low maintenance dose was associated with the Variant (AG + AA)/Wild (*1/*1). ( value <0.001). CYP2C9 variant was a risk factor for supratherapeutic INR in the multivariate logistic regression model. Thromboembolic complication and incidence of supratherapeutic INR were observed in patients carrying combined VKORC1 Variant (AG + AA) and CYP2C9 Variant (*2/*3). Data from our study suggest that together with clinical factors, VKORC1 and CYP2C9 polymorphisms are important contributors to warfarin dosing and may help predict adverse effects in Egyptian patients.
华法林是慢性预防血栓栓塞事件最常用的药物，在引起严重不良事件的药物中也名列前茅。剂量需求的变异性归因于医学、个人和遗传因素的个体差异。细胞色素P-450 2C9是通过催化药理活性更强的S-对映体转化为其无活性代谢产物来终止华法林抗凝作用的主要酶。华法林通过抑制维生素K环氧化物还原酶发挥作用。该蛋白由维生素K环氧化物还原酶复合体亚基1基因（VKORC1）编码。本研究旨在调查CYP2C9和VKORC1基因多态性对华法林治疗患者反应的药物遗传学影响。纳入了100例开始接受华法林治疗的患者和20例健康对照。根据患者的病历计算华法林的平均日剂量。对于每位患者，在纳入研究之前，对于以下适应症（深静脉血栓形成、肺栓塞、脑血管意外和心肌梗死）之一，至少3个月内华法林剂量的变异性小于10%且国际标准化比值（INR）在治疗目标范围内。采用四引物扩增阻滞突变系统PCR检测CYP2C92、CYP2C93和VKORC1 1639 G>A基因多态性。采用快速荧光法测定血浆华法林浓度。血浆华法林浓度范围为2.19至10.98μg/ml，中位数为3.52μg/ml。11%的病例观察到INR高于治疗范围。7%的病例发生血栓栓塞并发症，8%的病例发生大出血。高维持剂量（>7mg/天）与非VKORC12和纯合野生型CYP2C9（CYP2C91*1）等位基因组合相关，而低维持剂量与变异型（AG+AA）/野生型（*1/*1）相关（P值<0.001）。在多因素逻辑回归模型中，CYP2C9变异是INR高于治疗范围的危险因素。携带VKORC1变异（AG+AA）和CYP2C9变异（*2/*3）组合的患者观察到血栓栓塞并发症和INR高于治疗范围的发生率。我们的研究数据表明，与临床因素一起，VKORC1和CYP2C9多态性是华法林剂量的重要影响因素，可能有助于预测埃及患者的不良反应。
