Genetic Factors Influencing Warfarin Dose

影响华法林剂量的遗传因素

• 批准号: 7156977
• 负责人: MARK J RIEDER
• 金额: $ 39.69万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-01-01 至 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7156977
• 关键词: Accounting; Age; Anticoagulants; Anticoagulation; Bioinformatics; Blood Coagulation Factor; CYP1A2 gene; CYP2C19 gene; CYP2C9 gene; CYP3A4 gene; Candidate Disease Gene; Clinical; Complex; DNA Resequencing; Disease; Dose; Drug Kinetics; Enzymes; European; Event; Genes; Genetic; Genetic Determinism; Genetic Polymorphism; Genetic Variation; Goals; Haplotypes; Health Care Costs; Hemorrhage; Individual; International Normalized Ratio; Knowledge; Maintenance; Molecular; Monitor; NAD(P)H dehydrogenase (quinone) 1, human; NQO1 gene; Operative Surgical Procedures; Oral; Outcome; Patient Care; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacogenomics; Phase; Physicians; Plague; Population; Population Control; Population Study; Protein C; Proteins; Prothrombin time assay; Range; Research Personnel; Risk; Silicon Dioxide; Single Nucleotide Polymorphism; Standards of Weights and Measures; Structure; Study Section; Testing; Therapeutic; Therapeutic Index; Time; Universities; Variant; Vitamin K; Warfarin; Washington; Work; Writing; authority; cohort; day; design; genetic variant; insight; member; novel; prescription document; prescription procedure; prospective; reduced vitamin K; response; sex; size; vitamin K1 oxide

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.

描述（由申请人提供）：本项目的目标是将药物基因组学应用于华法林治疗，并获得对这种药物的总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。华法林是治疗血栓栓塞性疾病和手术后最常用的口服抗凝剂。在开始抗凝治疗和确定长期维持剂量期间，医生面临的严重困难之一是尽量减少过度出血的风险。因此，在治疗的起始阶段及以后，持续监测患者的凝血酶原时间（或国际标准化比值- INR）。预测-先验-个体的正确维持剂量的能力有望彻底改变患者护理并大幅降低医疗成本。我们已经定量了华法林剂量的两个关键遗传决定因素的影响，即VKORC 1和CYP 2C 9基因的多态性。加上患者年龄、性别和伴随药物的知识，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VKORC 1基因表达的遗传变异。在本项目中，我们将探索其他关键候选基因的单核苷酸多态性（SNPs）与华法林维持剂量之间的关系。本提案的长期目标是解释华法林剂量的100%个体间变异性。