Pharmacogenetics of ADRs: Warfarin Toxicity

ADR 的药物遗传学：华法林毒性

• 批准号: 6875574
• 负责人: Allan Edward Rettie
• 金额: $ 34.72万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6875574
• 关键词: Hispanic Americans; blood coagulation; caucasian American; clinical research; cytochrome P450; drug adverse effect; drug metabolism; enzyme activity; gene deletion mutation; genetic polymorphism; genetic promoter element; human genetic material tag; human tissue; nucleoproteins; pharmacogenetics; racial /ethnic difference; reporter genes; transfection; warfarin

DESCRIPTION (provided by applicant): The Iong-term aim of this research is to determine the clinical consequences of genetic variability within the human CYP2C9 gene among subjects of diverse ethnic origins, and to understand molecular mechanisms that underlie genetically-based alterations in the functional activity of the CYP2C9 enzyme. CYP2C9 is a major human liver form of P450 that metabolizes approximately 15% of all drugs that are cleared by phase I processes. It is well established that treating patients that possess the common CYP2C9*2 and CYP2C9*3 variants with low therapeutic index drugs, e.g. warfarin, has clinically important implications. These are adverse drug reactions (ADRs) due to over-medication that can result in significant, but potentially avoidable, patient health costs. Although a large body of information exists for certain CYP2C9 polymorphisms in Caucasian subjects, the full spectrum of genetic variation at the CYP2C9 locus, and attendant functional consequences, is poorly defined. Moreover, other important ethnic groups in the US, notably Hispanics, have been quite neglected in this research area, despite evidence for population-specific polymorphisms in the CYP2C9 gene. Therefore, we will; Specific Aim 1: Identify the spectrum of distal regulatory polymorphisms that exist at the CYP2C9 locus. SNP discovery will be performed in a panel of 90 DNA samples from the Polymorphism Discovery Resource. SNP validation and allele frequency determinations will then be carried out in White and Hispanic populations. Specific Aim 2: Determine the functional significance of new promoter and coding-region polymorphisms in CYP2C9. Mechanisms underlying changes in function will be probed with reporter constructs, deletion analysis, DNA/binding protein assays, recombinantly expressed proteins and stably-transfected cell lines. Specific Aim 3: Determine the impact of new CYP2C9 polymorphisms on anticoagulation-related outcomes in previously phenotyped Caucasian patients by resequencing across 60 kbp of the CYP2C9 gene from 185 pre-existing warfarin patient DNA samples. Aims 1 and 2 will test the hypothesis that; novel, functionally important polymorphisms remain to be elucidated within the CYP2C9 locus, some of which will be population-selective. Aim 3 will test the hypothesis that; promoter-region SNPs in the CYP2C9 gene are a determinant of warfarin dose. Successful completion of these studies will impact the ability of clinicians to predict the likelihood of adverse drug reactions to warfarin, and other drugs that are CYP2C9 substrates, arising in minority populations.

描述（由申请人提供）：这项研究的IONG术语目的是确定人类CYP2C9基因在不同种族起源受试者中的遗传变异性的临床后果，并了解基于CYP2C9酶功能活性基于遗传学的变化的分子机制。 CYP2C9是P450的主要人类肝脏形式，它代谢了通过I期工艺清除的所有药物中约15％。众所周知，治疗具有常见CYP2C9*2和CYP2C9*3的患者具有低治疗指数药物的变体，例如华法林在临床上具有重要意义。这些是由于过度服用的过度药物而导致的不良药物反应（ADR），可能会导致重大但可能避免的患者健康成本。尽管在高加索受试者中存在某些CYP2C9多态性的大量信息，但CYP2C9基因座的遗传变异的全部差异和随之而来的功能后果的定义很差。此外，尽管有证据表明CYP2C9基因中人群特异性的多态性证据，但在美国，其他重要的种族，尤其是西班牙裔群体也被忽略了。因此，我们将； 具体目标1：确定CYP2C9基因座存在的远端调节多态性的光谱。 SNP Discovery将在多态性发现资源的90个DNA样品小组中进行。然后将在白人和西班牙裔人群中进行SNP验证和等位基因频率确定。 具体目标2：确定CYP2C9中新启动子和编码区多态性的功能意义。功能变化的机制将通过报告基因构建体，缺失分析，DNA/结合蛋白测定，重组表达的蛋白质和稳定转染的细胞系进行探测。 具体目的3：通过从185个前存在的WARFARIN患者DNA样品中重新定制CYP2C9基因的60 KBP，确定新的CYP2C9多态性对先前表型高加索患者抗凝相关结果的影响。 目标1和2将检验以下假设。新型，功能上重要的多态性在CYP2C9基因座中仍有待阐明，其中一些将是种群选择性的。 AIM 3将检验以下假设。 CYP2C9基因中的启动子区SNP是华法林剂量的决定因素。这些研究的成功完成将影响临床医生预测对华法林的不良药物反应的可能性以及其他是CYP2C9底物的药物，这是少数群体中引起的。