A polymorphism in the VKORC1 gene is associated with an interindividual variability in the dose-anticoagulant effect of warfarin
A polymorphism in the VKORC1 gene is associated with an interindividual variability in the dose-anticoagulant effect of warfarin
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DOI：
10.1182/blood-2004-06-2111
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发表时间：
2005-01-15
期刊：
影响因子：
20.3
通讯作者：
Margaglione, M
中科院分区：
文献类型：
--
作者：
D'Andrea, G;D'Ambrosio, RL;Margaglione, M
患者需要不同的华法林剂量来达到治疗抗凝的目标。这种变异很大程度上是由遗传决定的，它只能部分地用细胞色素CYP2C9位点的遗传变异来解释。在147例开始使用华法林抗凝治疗的患者中，我们研究了VKORC1基因突变是否会影响为获得目标抗凝强度而开的药物剂量。鉴定出两个同义突变，分别是Cys43位点的129C b> T和Leu120位点的3462C>T，以及2个错义突变，Asp38Tyr和Arg151Gln。没有发现这些突变影响华法林处方的个体间变异性。最后，发现了2个共同多态性，1号内含子1173C>T和3'非翻译区（UTR） 3730G>A过渡。无论是否存在混杂变量，VKORC1 1173CC基因型患者所需华法林的平均调整剂量（6.2 mg）高于携带CT （4.8 mg, P = 0.002）或TT基因型患者（3.5 mg, P < 0.001）。在目前的情况下，研究的VKORC1和CYP2C9遗传变异约占个体间变异的三分之一（r(2), 0.353）。VKORC1基因位点的遗传变异可调节为获得目标抗凝强度而规定的平均日剂量。
Patients require different warfarin dosages to achieve the target therapeutic anticoagulation. The variability is largely genetically determined, and it can be only partly explained by genetic variability in the cytochrome CYP2C9 locus. In 147 patients followed from the start of anticoagulation with warfarin, we have investigated whether VKORC1 gene mutations have affected doses of drug prescribed to acquire the target anticoagulation intensity. Two synonymous mutations, 129C>T at Cys43 and 3462C>T at Leu120, and 2 missense mutations, Asp38Tyr and Arg151Gln,were identified. None of these mutations was found to affect the interindividual variability of warfarin prescribed. Finally, 2 common polymorphisms were found, 1173C>T in the intron 1 and 3730G>A transition in the 3' untranslated region (UTR). Regardless of the presence of confounding variables, the mean adjusted dose required of warfarin was higher (6.2 mg) among patients with the VKORC1 1173CC genotype than those of patients carrying the CT (4.8 mg; P = .002) or the TT genotype (3.5 mg: P < .001). In the present setting, VKORC1 and CYP2C9 genetic variants investigated accounted for about a third (r(2), 0.353) of the interindividual variability. Genetic variants of the VKORC1 gene locus modulate the mean daily dose of drug prescribed to acquire the target anticoagulation intensity.