Genetic Factors Influencing Warfarin Dose

描述（由申请人提供）：该项目的目标是将药物基因组学应用于华法林治疗，并获得对华法林药物反应的整体个体间遗传变异的新见解，从而使这种抗凝剂的前瞻性、个体化治疗成为现实。华法林是最常用的口服抗凝剂，用于治疗血栓栓塞性疾病和手术后。在抗凝治疗的开始和确定长期维持剂量时，医生面临的一个严重困难是尽量减少过度出血的风险。因此，患者的凝血酶原时间（或国际标准化比率- INR）在治疗开始阶段及以后持续监测。先验地预测个人正确的维持剂量的能力有望彻底改变病人护理，并大幅降低医疗成本。我们量化了华法林剂量的两个关键遗传决定因素的影响，即VKORC1和CYP2C9基因的多态性。再加上对患者年龄、性别和伴随用药的了解，现在可以解释欧洲血统人群中约50%的华法林剂量变异性，其中约25%是由于影响VKORC1基因表达的遗传变异。在本项目中，我们拟探讨其他关键候选基因的单核苷酸多态性（snp）与华法林维持剂量的关系。该建议的长期目标是100%解释华法林剂量的个体间差异。

DESCRIPTION (provided by applicant): The goal of this project is to apply pharmacogenomics to warfarin therapy, and gain new insights into the overall inter-individual genetic variation in response to this drug, so that prospective, individualized treatment with this anticoagulant becomes a reality. Warfarin is the most commonly employed oral anticoagulant used to treat thromboembolic disease and following surgery. One of the serious difficulties faced by physicians during both initiation of anticoagulation therapy and in determining a long-term maintenance dose is minimizing the risk of excessive bleeding. Consequently, patients have their prothrombin time (or international normalized ratio - INR) continuously monitored during the initiation phase of treatment and beyond. The ability to predict - a priori - the correct maintenance dose for an individual could be expected to revolutionize patient care and drastically cut healthcare costs. We have quantitated the effect of two critical genetic determinants of warfarin dose i.e. polymorphisms in the VKORC1 and CYP2C9 genes. Together with knowledge of patient age, sex, and concomitant drug medications, about 50% of the variability in warfarin dosing can now be accounted for in European ancestry populations, about 25% of which is due to genetic variants influencing expression of the VKORC1 gene. In this project, we propose to explore the relationship between single nucleotide polymorphisms (SNPs) in other key candidate genes and their association with warfarin maintenance dose. The long-term aim of this proposal is to account for 100% of the inter-individual variability in warfarin dosing.