A daily dose of vitamin K antagonists (VKAs) may vary and its range depends on various interrelated factors. Low responsiveness to VKA (defined as a failure to achieve a target international normalized ratio [INR]) is associated with polymorphisms of the vitamin K epoxide reductase-oxidase complex gene (VKORC1). A highly prevalent promoter single-nucleotide polymorphism (VKORC1−1639 G>A, rs 17878363) impairsVKORC1 expression and determines the interindividual variability of the target INR. We studied 57 patients receiving oral anticoagulation, including 50 subjects treated with acenocoumarol (mean dose: 5.7±2.3 mg/day) and 7 treated with warfarin (mean dose: 9.6±4.2 mg/day). The indications for the use of oral anticoagulant therapy were as follows: deep-vein thrombosis (N = 23); pulmonary embolism (N = 20); arterial thrombosis (N = 5); stroke (N = 4); atrial fibrillation with transient ischemic attacks (N = 2), and history of multiple thromboembolic events (N = 3). Identification of theVKORC1 genomic variation was performed using DNA sequencing methods. The prevalence of the mutated allele (VKORC1-1639A) was 41%. TheVKORC1-1639G allele carriers required a higher daily dose of acenocoumarol (5.9±1.9 mg) than the noncarriers (4.1±3.3 mg;P < 0.001). All of 5 low responders (who failed to achieve a target INR using standard dose requirements of VKAs) were homozygous for the 1639G allele. Low responders did not differ from good responders with respect to age, gender, and body mass index. Our findings suggest the potential benefits from pharmacogenetic testing, and provide evidence that theVKORC1 −1639 G>A gene polymorphism may explain at least in part the low responsiveness to acenocoumarol.

中文翻译：

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维生素 K 环氧化物还原酶-氧化酶复合物基因多态性 (-1639G>A) 和维生素 K 拮抗剂剂量效应的个体差异。

维生素 K 拮抗剂 (VKA) 的每日剂量可能会有所不同，其范围取决于各种相关因素。对 VKA 的低反应性（定义为未能达到目标国际标准化比率 [INR]）与维生素 K 环氧化物还原酶-氧化酶复合基因 ( VKORC1 ) 的多态性有关。高度流行的启动子单核苷酸多态性 (VKORC1−1639 G>A, rs 17878363) 会损害VKORC1表达并决定目标 INR 的个体间变异性。我们研究了 57 名接受口服抗凝治疗的患者，其中 50 名接受醋硝香豆素治疗（平均剂量：5.7±2.3 毫克/天）和 7 名接受华法林治疗（平均剂量：9.6±4.2 毫克/天）。口服抗凝治疗的适应证如下：深静脉血栓形成（N= 23); 肺栓塞（N = 20）；动脉血栓形成（N = 5）；中风（N = 4）；房颤伴短暂性脑缺血发作 ( N = 2) 和多发血栓栓塞事件史 ( N = 3)。VKORC1基因组变异的鉴定是使用 DNA 测序方法进行的。突变的等位基因（的流行VKORC1 -1639A）为41％。所述VKORC1 -1639G等位基因携带者需要醋硝香豆素（5.9±1.9毫克），比非携带者（4.1±3.3毫克的较高日剂量; P <0.001）。所有 5 名低反应者（使用 VKA 的标准剂量要求未能达到目标 INR）均为 1639G 等位基因纯合子。低反应者与良好反应者在年龄、性别和体重指数方面没有区别。我们的研究结果表明药物遗传学测试的潜在益处，并提供证据表明VKORC1 -1639 G>A 基因多态性可以至少部分解释对醋硝香豆素的低反应性。