A multi-factorial analysis of response to warfarin in a UK prospective cohort.
A multi-factorial analysis of response to warfarin in a UK prospective cohort.
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DOI：
10.1186/s13073-015-0255-y
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发表时间：
2016-01-06
期刊：
影响因子：
12.3
通讯作者：
Pirmohamed M
中科院分区：
文献类型：
--
作者：
Bourgeois S;Jorgensen A;Zhang EJ;Hanson A;Gillman MS;Bumpstead S;Toh CH;Williamson P;Daly AK;Kamali F;Deloukas P;Pirmohamed M
华法林是世界范围内应用最广泛的口服抗凝剂，但其治疗指标较窄，需要持续监测抗凝反应。先前的全基因组研究侧重于确定稳定剂量差异的解释因素，但尚未探讨患者对华法林的初始反应，以及影响华法林初始和稳定剂量的更广泛的临床和生化因素。对711例开始使用华法林的患者进行为期6个月的随访，重点分析非遗传因素和遗传因素。结果测量为第一周华法林平均周剂量（MWD）、稳定平均周剂量（SMWD）和国际标准化比值（INR） bb0.4。样品在Illumina Human610-Quad芯片上进行基因分型。使用Plink和r进行统计学分析。VKORC1和CYP2C9是华法林MWD和SMWD的主要遗传决定因素，CYP4F2的影响较小。年龄，身高，体重，吸烟和相互作用的药物占不到20%的差异。我们的多因素分析分别解释了57.89%和56.97%的MWD和SMWD变异。VKORC1和CYP2C9*3基因型、年龄、身高和体重，以及其他临床因素，如饮酒、负荷剂量和伴随药物，对华法林的初始INR反应很重要。在可获得数据的一小部分患者中，凝血因子VII和IX的水平（高度相关）也起了作用。我们在前瞻性招募队列中的多因素分析表明，多种因素，遗传和临床，在决定华法林的反应中是重要的。VKORC1和CYP2C9基因多态性是华法林剂量的最重要决定因素，发现影响华法林剂量的其他临床重要常见变异的可能性很小。VKORC1和CYP2C9*3都是华法林初始INR反应的重要决定因素。其他未达到全基因组意义的新变异被确定为不同的结果测量，但需要复制。本文的在线版本（doi:10.1186/s13073-015-0255-y）包含补充材料，授权用户可以使用。
Warfarin is the most widely used oral anticoagulant worldwide, but it has a narrow therapeutic index which necessitates constant monitoring of anticoagulation response. Previous genome-wide studies have focused on identifying factors explaining variance in stable dose, but have not explored the initial patient response to warfarin, and a wider range of clinical and biochemical factors affecting both initial and stable dosing with warfarin. A prospective cohort of 711 patients starting warfarin was followed up for 6 months with analyses focusing on both non-genetic and genetic factors. The outcome measures used were mean weekly warfarin dose (MWD), stable mean weekly dose (SMWD) and international normalised ratio (INR) > 4 during the first week. Samples were genotyped on the Illumina Human610-Quad chip. Statistical analyses were performed using Plink and R. VKORC1 and CYP2C9 were the major genetic determinants of warfarin MWD and SMWD, with CYP4F2 having a smaller effect. Age, height, weight, cigarette smoking and interacting medications accounted for less than 20 % of the variance. Our multifactorial analysis explained 57.89 % and 56.97 % of the variation for MWD and SMWD, respectively. Genotypes for VKORC1 and CYP2C9*3, age, height and weight, as well as other clinical factors such as alcohol consumption, loading dose and concomitant drugs were important for the initial INR response to warfarin. In a small subset of patients for whom data were available, levels of the coagulation factors VII and IX (highly correlated) also played a role. Our multifactorial analysis in a prospectively recruited cohort has shown that multiple factors, genetic and clinical, are important in determining the response to warfarin. VKORC1 and CYP2C9 genetic polymorphisms are the most important determinants of warfarin dosing, and it is highly unlikely that other common variants of clinical importance influencing warfarin dosage will be found. Both VKORC1 and CYP2C9*3 are important determinants of the initial INR response to warfarin. Other novel variants, which did not reach genome-wide significance, were identified for the different outcome measures, but need replication. The online version of this article (doi:10.1186/s13073-015-0255-y) contains supplementary material, which is available to authorized users.