Pharmacogenetics of ADRs: Warfarin Toxicity

ADR 的药物遗传学：华法林毒性

• 批准号: 7668284
• 负责人: Allan Edward Rettie
• 金额: $ 14.21万
• 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 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7668284
• 关键词: Address; Adverse reactions; Affinity; Alleles; Anticoagulation; Applications Grants; Area; Biological Assay; CYP2C9 gene; Caucasians; Caucasoid Race; Cell Line; Clinical; Code; Cytochrome P450; DNA; DNA Resequencing; DNA-Binding Proteins; Distal; Dose; Enzymes; Ethnic Origin; Ethnic group; Event; Exons; Gene Frequency; Genetic; Genetic Polymorphism; Genetic Variation; Genomics; Goals; Haplotypes; Health Care Costs; Hispanics; Human; In Vitro; Incidence; Individual; Ligands; Liver; Measures; Minority; Minority Groups; Molecular; Outcome; Oxidoreductase; Patients; Personal Satisfaction; Pharmaceutical Preparations; Pharmacogenetics; Phase; Phenotype; Phenytoin; Population; Process; Promoter Regions; Protein Binding; Proteins; Proteomics; Reaction; Recombinant Proteins; Reporter; Reporting; Research; Research Personnel; Resources; Sampling; Single Nucleotide Polymorphism; Structure; Testing; Therapeutic Index; Tolbutamide; Toxic effect; United States; Validation; Variant; Warfarin; base; deletion analysis; drug metabolism; functional genomics; genetic linkage analysis; in vivo; mRNA Stability; neglect; novel; programs; promoter; translational study

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）：本研究的长期目标是确定不同种族起源的受试者中人类 CYP2C9 基因内遗传变异的临床后果，并了解 CYP2C9 酶功能活性基于遗传的改变的分子机制。 CYP2C9 是 P450 的主要人类肝脏形式，可代谢 I 期过程清除的所有药物中约 15%。众所周知，使用低治疗指数药物治疗具有常见 CYP2C9*2 和 CYP2C9*3 变异的患者，例如华法林具有重要的临床意义。这些是由于过度用药而导致的药物不良反应 (ADR)，可能会导致患者承受巨大但可能可以避免的健康成本。尽管存在大量有关白种人受试者中某些 CYP2C9 多态性的信息，但 CYP2C9 位点遗传变异的全谱以及随之而来的功能后果尚不清楚。此外，尽管有证据表明 CYP2C9 基因存在人群特异性多态性，但美国其他重要种族群体，尤其是西班牙裔，在这一研究领域却被严重忽视。因此，我们会； 具体目标 1：确定 CYP2C9 基因座上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 90 个 DNA 样本组中进行。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测定。 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。将通过报告构建体、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来探究功能变化的机制。 具体目标 3：通过对 185 名先前存在的华法林患者 DNA 样本中 60 kbp 的 CYP2C9 基因进行重新测序，确定新的 CYP2C9 多态性对先前表型白种人患者的抗凝相关结果的影响。 目标 1 和 2 将检验以下假设： CYP2C9 位点内新的、功能上重要的多态性仍有待阐明，其中一些多态性将具有群体选择性。目标 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华法林和其他 CYP2C9 底物药物在少数人群中出现药物不良反应可能性的能力。