Building individualized medicine: Prevention of adverse reactions to warfarin therapy
Building individualized medicine: Prevention of adverse reactions to warfarin therapy
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DOI：
10.1124/jpet.106.117952
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发表时间：
2007-08-01
影响因子：
3.5
通讯作者：
McDonnell, Patrick
中科院分区：
文献类型：
--
作者：
Krynetskiy, Evgeny;McDonnell, Patrick
华法林是世界上使用最广泛的口服抗凝剂，用于静脉血栓、肺栓塞、慢性心房颤动和人工心脏瓣膜患者。大约有30个基因参与了华法林的治疗作用，这些基因的遗传多态可能调节其抗凝血活性。与单基因药物遗传特征不同，华法林药物反应是一种多基因特征，开发预测华法林不良反应的诊断工具需要一种新的方法。结合两种策略，即等位基因变异的生化分离和连锁不平衡关联研究，找到候选基因中的遗传多态与华法林反应之间的关联。6个基因的遗传多态与华法林抗凝作用的个体差异密切相关，其中VKORC1、CYP2C9、proc、EPHX1、GGCX和ORM1与华法林抗凝作用的个体差异有很强的相关性，最强的预测因子是VKORC1和CYP2C9。基于单核苷酸多态性(SNP)的致密遗传图谱的生成使识别与药物反应表型相关的单倍型成为可能。与华法林剂量表型相关的单倍型之间的区别可以通过一组有限的信息性多态(标签SNPs)来实现。标签SNPs在药物基因组分析中的应用为剖析药物反应的多基因特征提供了一个很有前途的工具。
Warfarin is the most widely used oral anticoagulant in the world for patients with venous thrombosis, pulmonary embolism, chronic atrial fibrillation, and prosthetic heart valves. Approximately 30 genes contribute to therapeutic effects of warfarin, and genetic polymorphisms in these genes may modulate its anticoagulant activity. In contrast to monogenic pharmacogenetic traits, warfarin drug response is a polygenic trait, and development of diagnostic tools predictive of adverse reactions to warfarin requires a novel approach. A combination of two strategies, biochemical isolation of allelic variants and linkage disequilibrium association studies, was used to find an association between genetic polymorphisms in the candidate genes and warfarin response. A strong association was found between genetic polymorphisms in six genes, including VKORC1, CYP2C9, PROC, EPHX1, GGCX, and ORM1, and interindividual variability in the anticoagulant effect of warfarin; the strongest predictors were VKORC1 and CYP2C9. Generation of single nucleotide polymorphism (SNP)-based dense genetic maps made it possible to identify haplotypes associated with drug-response phenotypes. Discrimination between haplotypes associated with warfarin dose phenotypes can be achieved by a limited set of informative polymorphisms (tag SNPs). The use of tag SNPs in pharmacogenomic analysis provides a promising tool for dissecting polygenic traits of drug response.