VKORC1 and CYP2C9 genotype and patient characteristics explain a large proportion of the variability in warfarin dose requirement among children
VKORC1 and CYP2C9 genotype and patient characteristics explain a large proportion of the variability in warfarin dose requirement among children
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DOI：
10.1182/blood-2011-08-372722
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发表时间：
2012-01-19
期刊：
影响因子：
20.3
通讯作者：
Kamali, Farhad
中科院分区：
文献类型：
--
作者：
Biss, Tina T.;Avery, Peter J.;Kamali, Farhad
虽然遗传和环境因素解释了大约一半的成人华法林剂量需求的个体间变异性，但在儿童中可用的信息有限。在一项对来自5个三级医疗中心的抗凝儿童的横断面研究中，对120名华法林剂量稳定的儿童进行了VKORC 1（-1639G > A; rs 9923231）、CYP 2C 9（*2和 *3等位基因; rs 1799853和rs 1057910）和CYP 4F 2（V433 M; rs 2108622）多态性的基因分型。记录临床和人口统计学特征。数据的多元回归分析显示，尽管CYP 4F 2对剂量模型没有贡献，但华法林剂量需求的72.4%变异性归因于患者身高、VKORC 1和CYP 2C 9的遗传多态性以及华法林适应症。最近发表的国际华法林药物遗传学联盟基于药物遗传学的华法林剂量算法（基于来自抗凝成人的数据）始终高估了我们儿童队列的华法林剂量。与成人患者相比，儿童患者华法林剂量的个体间变异性的相似比例可由遗传因素解释，尽管身高在儿童中是一个更大的预测因素。华法林给药的药物基因组学方法有可能提高儿童华法林治疗的疗效和安全性。然而，如果要实现其潜在的益处，则算法应来自儿童的数据。（血。2012;119（3）：868-873）
Although genetic and environmental factors explain approximately half of the interindividual variability in warfarin dose requirement in adults, there is limited information available in children. In a cross-sectional study of anticoagulated children from 5 tertiary care centers, 120 children with a stable warfarin dose were genotyped for VKORC1 (-1639G > A; rs9923231), CYP2C9 (*2 and *3 alleles; rs1799853 and rs1057910), and CYP4F2 (V433M; rs2108622) polymorphisms. Clinical and demographic features were recorded. Multiple regression analysis of the data showed that, although CYP4F2 made no contribution to the dose model, 72.4% of the variability in warfarin dose requirement is attributed to by patient height, genetic polymorphisms in VKORC1 and CYP2C9, and indication for warfarin. The recently published International Warfarin Pharmacogenetics Consortium pharmacogenetic-based warfarin dosing algorithm (based on data derived from anticoagulated adults) consistently overestimated warfarin dose for our cohort of children. A similar proportion of the interindividual variability in warfarin dose is explained by genetic factors in children compared with adult patients, although height is a greater predictor in children. A pharmacogenomic approach to warfarin dosing has the potential to improve the efficacy and safety of warfarin therapy in children. However, algorithms should be derived from data in children if their potential benefit is to be realized. (Blood. 2012;119(3):868-873)