Hepatitis C: host determinants of progression and respo*

丙型肝炎：进展和反应的宿主决定因素*

• 批准号: 6517973
• 负责人: Huiying Yang
• 金额: $ 47.5万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6517973
• 关键词: African American; caucasian American; chronic disease /disorder; clinical trials; combination chemotherapy; gene environment interaction; gene interaction; genetic markers; genetic polymorphism; genotype; hepatitis C; hepatitis C virus; human subject; human therapy evaluation; immunogenetics; immunoglobulin genes; interferon alpha; microorganism disease chemotherapy; pathologic process; patient oriented research; pharmacogenetics; phenotype; ribavirin; statistics /biometry; virus genetics; virus infection mechanism

DESCRIPTION (provided by applicant): In the United States, approximately 2.7 million people have chronic hepatitis C virus (HCV) infection, which is a significant clinical, social, and economic burden for the infected individual and for society as a whole. The outcome of a viral infection is determined by the interaction between the virus and the host immune response. Host genetic factors may also contribute to observed differences in disease prevalence, progression, and treatment response between the African American (AA) and non-Hispanic white (white) populations. Thus, we propose a comprehensive pharmacogenetic study to test the hypothesis that host genetic factors contribute to treatment response and disease progression of HCV infected individuals by examining a large number of immunological candidate genes. Specifically, we propose a two-stage design: initial testing with polymorphic markers spacing at 3-5kb for each of 15 candidate genes, followed by fine mapping of those genes selected based on statistical significance levels, number of significant markers, and results from a second sample. Three sets of samples will be used to evaluate response to therapy and/or disease progression: patients enrolled in the Virahep C trial (N=400), patients excluded from the trial but with disease progression information (N=400), and patients studied at NIDDK Liver Disease Section (N=400). The genetic association results from the latter sample will aid in decision making as to which genes to follow-up with fine mapping. We will also utilize multiple analytic approaches to evaluate associations between candidate genes and outcome variables: evaluating gene-gene interaction, and gene-viral/environmental factor interaction. In addition, we have built in strategies for controlling population stratification by genotyping additional population specific markers and evaluating population structure. By covering important candidate genes comprehensively, utilizing several samples, and explicitly testing possible confounding factors, this proposal maximizes the opportunity to identify the genes and their variants that contribute to the response to therapy and disease progression in HCV infection. As a result of identifying these host factors genetically and investigating their molecular interactions with HCV, we may gain additional insights into HCV pathogenesis and uncover new potential targets for vaccine development and therapy.

描述（由申请人提供）： 在美国，大约有270万人患有慢性丙型肝炎 病毒（HCV）感染，这是一种重要的临床，社会和经济 受感染者和整个社会的负担。一个结果 病毒感染取决于病毒与宿主之间的相互作用 免疫反应。宿主遗传因素也可能有助于观察到 疾病患病率，进展和治疗反应的差异 非裔美国人（AA）和非西班牙裔白人（白色）人群。因此，我们 提出了一项全面的药物遗传学研究，以检验宿主的假设 遗传因素有助于HCV的治疗反应和疾病进展 通过检查大量免疫候选者感染个人 基因。 具体而言，我们提出了两阶段的设计：用多态性的初始测试 15个候选基因的标记间距为3-5kb，然后是细。 基于统计显着性水平选择的那些基因的映射， 显着标记的数量，以及第二个样本的结果。三组 样品将用于评估对治疗和/或疾病的反应 进展：参加Virahep C试验的患者（n = 400），患者 排除在试验之外，但具有疾病进展信息（n = 400），并且 在NIDDK肝病部门学习的患者（n = 400）。遗传 后一个样本的关联结果将有助于决策 哪些基因进行了细微的映射。我们还将利用多个 评估候选基因与候选基因之间关联的分析方法 结果变量：评估基因 - 基因相互作用和 基因病毒/环境因子相互作用。此外，我们内置了 通过基因分型来控制人口分层的策略 人群特定标记和评估人口结构。 通过全面涵盖重要的候选基因，利用几个 样品，并明确测试可能的混杂因素，该提案 最大化识别基因及其变体的机会 有助于对HCV感染中治疗和疾病进展的反应。 由于从遗传上识别这些宿主因素并研究 它们与HCV的分子相互作用，我们可能会获得更多的见解 发病机理并发现了疫苗开发的新潜在靶标 治疗。