Pharmacodynamic resistance to warfarin associated with a Val66Met substitution in vitamin K epoxide reductase complex subunit 1
Pharmacodynamic resistance to warfarin associated with a Val66Met substitution in vitamin K epoxide reductase complex subunit 1
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与维生素 K 环氧化物还原酶复合物亚基 1 中 Val66Met 取代相关的华法林药效学耐药性
DOI：
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发表时间：
2004
影响因子：
6.7
通讯作者：
A. Mumford
中科院分区：
文献类型：
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作者：
D. Harrington;Sarah Underwood;C. Morse;M. Shearer;E. Tuddenham;A. Mumford
摘要最近发现了编码维生素K环氧化物还原酶复合体1亚单位(VKORC1)的基因，它是华法林的治疗靶点。为了探讨VKORC1基因与华法林剂量反应的关系，我们对华法林耐药患者的VKORC1基因进行了研究。从820例患者中，我们鉴定出4名患者每天需要超过25 mg的华法林进行抗凝治疗，其中3名患者的血清华法林浓度在0.70-2.3 mg/L的治疗范围内，并显示出野生型VKORC1.第4例华法林耐药个体的血清华法林浓度持续较高(≥为5.7 mg/L)，但临床上尚无可识别的华法林耐药原因。VKORC1196G杂合子→A突变预测VKORC1多肽中存在Val66Met替换。在2名从未接受华法林治疗的无症状家庭成员中也发现了这种转变。这些个体具有正常的维生素K依赖凝血因子活性，血清中未检测到PIVKAII和维生素K12，3环氧化物，这表明他们的基础维生素K环氧化物还原酶活性没有受到VKORC1Val66Met替换的不利影响。VKORC1的核苷酸转换与华法林药效学耐药之间的关联支持了VKORC1是华法林作用部位的假说，并表明VKORC1序列是华法林剂量反应的重要决定因素。
Summary The gene encoding vitamin K epoxide reductase complex subunit 1 (VKORC1), a component of the enzyme that is the therapeutic target site for warfarin, has recently been identified. In order to investigate the relationship betweenVKORC1 and warfarin dose response, we studied theVKORC1 gene (VKORC1) in patients with warfarin resistance. From a study group of 820 patients, we identified 4 individuals who required more than 25 mg of warfarin daily for therapeutic anticoagulation.Three of these had serum warfarin concentrations within the therapeutic range of 0.7–2.3 mg/l and showed wild-type VKORC1 sequence. The fourth warfarin resistant individual had consistently high ( ≥ 5.7 mg/l) serum warfarin concentrations, yet had no clinically discernible cause for warfarin resistance. VKORC1 showed a heterozygous 196G→ A transition that predicted aVal66Met substitution in the VKORC1 polypeptide. This transition was also identified in 2 asymptomatic family members who had never received warfarin.These individuals had normal vitamin-K dependent coagulation factor activities and undetectable serum PIVKAII and vitamin K 1 2,3 epoxide suggesting that their basal vitamin K epoxide reductase activity was not adversely affected by the VKORC1 Val66Met substitution.The association between a nucleotide transition in VKORC1 and pharmacodynamic warfarin resistance supports the hypothesis that VKORC1 is the site of action of warfarin and indicates that VKORC1 sequence is an important determinant of the warfarin dose response.