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（由申请方提供）：本研究的长期目的是确定不同种族受试者中人CYP 2C 9基因内遗传变异的临床后果，并了解CYP 2C 9酶功能活性遗传性改变的分子机制。CYP 2C 9是P450的主要人类肝脏形式，其代谢约15%的通过I期过程清除的所有药物。已明确，使用低治疗指数药物（例如华法林）治疗具有常见CYP 2C 9 *2和CYP 2C 9 *3变体的患者具有临床重要意义。这些是由于过度用药导致的药物不良反应（ADR），可能导致显著但可能避免的患者健康成本。尽管高加索受试者中存在大量关于某些CYP 2C 9多态性的信息，但CYP 2C 9基因座的完整遗传变异谱以及随之而来的功能后果却定义不清。此外，美国其他重要的种族群体，特别是西班牙裔，在这一研究领域一直被忽视，尽管有证据表明CYP 2C 9基因存在人群特异性多态性。因此，我们将; 具体目标1：确定CYP 2C 9基因座存在的远端调控多态性谱。SNP发现将在来自多态性发现资源的一组90个DNA样本中进行。然后在白色和西班牙裔人群中进行SNP验证和等位基因频率测定。 具体目标2：确定CYP 2C 9新启动子和编码区多态性的功能意义。功能变化的潜在机制将通过报告基因构建体、缺失分析、DNA/结合蛋白测定、重组表达蛋白和稳定转染的细胞系进行探讨。 具体目标3：通过对185份既往华法林患者DNA样本的60 kbp CYP 2C 9基因进行重新测序，确定新的CYP 2C 9多态性对既往表型分析的白人患者抗凝相关结局的影响。 目的1和2将检验以下假设：CYP 2C 9基因座内的新的、功能重要的多态性仍有待阐明，其中一些多态性具有群体选择性。目的3将检验以下假设：CYP 2C 9基因启动子区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少数人群中华法林和其他CYP 2C 9底物药物不良反应可能性的能力。