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)：这项研究的长期目标是确定不同种族来源的受试者中人类CYP2C9基因遗传变异的临床后果，并了解基于遗传的CYP2C9酶功能活性变化的分子机制。CYP2C9是人类肝脏中P450的一种主要形式，在I期过程中被清除的所有药物中，约有15%是由其代谢的。公认的是，用低治疗指数药物，如华法林治疗具有常见的CYP2C9*2和CYP2C9*3变异的患者具有重要的临床意义。这些是由于过度用药而引起的药物不良反应(ADR)，可能会导致巨大的但潜在可以避免的患者健康成本。尽管在高加索人群中存在大量的关于某些CYP2C9基因多态的信息，但对该基因座的全部遗传变异以及伴随而来的功能后果的定义并不明确。此外，美国其他重要的种族群体，特别是西班牙裔，在这一研究领域被完全忽视，尽管有证据表明CYP2C9基因存在群体特有的多态。因此，我们会； 具体目标1：确定存在于CYP2C9基因座的远端调控多态的谱系。SNP发现将在一个由90个DNA样本组成的小组中进行，该样本来自多态发现资源。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测定。 特异性目的2：确定新启动子及其编码区基因多态性的功能意义。潜在的功能变化机制将通过报告构建、缺失分析、DNA/结合蛋白分析、重组表达的蛋白质和稳定转染的细胞系来探索。 具体目标3：通过对185例先前存在的华法林患者DNA样本中的60kbp的CYP2C9基因进行重新测序，确定新的CYP2C9基因多态对先前表型的高加索患者抗凝相关结局的影响。 目标1和目标2将检验这一假设，即新的、功能上重要的多态在CYP2C9基因座内仍有待阐明，其中一些将是群体选择性的。目的3将验证这样的假设：在CYP2C9基因的启动子区域SNPs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华法林和其他以CYP2C9为底物的药物在少数族裔人群中出现不良反应的可能性。