Clonal hematopoiesis and severity of COVID-19 disease

克隆造血和 COVID-19 疾病的严重程度

• 批准号: 10196497
• 负责人: KENNETH WALSH
• 金额: $ 33.66万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10196497
• 关键词: 2019-nCoV; Acute; Age; Area; Bar Codes; Biochemical; Bioinformatics; Blood; COVID-19; COVID-19 patient; COVID-19 severity; Cardiac; Cardiovascular Diseases; Cell physiology; Cells; Child; Clinical; Clinical Data; Clinical Research; Clonal Hematopoietic Stem Cell; Computer software; Computerized Medical Record; Consent; DNA; DNA sequencing; Data; Dependence; Development; Diabetes Mellitus; Disease; Doctor of Medicine; Doctor of Philosophy; Elderly; Enrollment; Exhibits; Gender; Genes; Heart Injuries; Hematology; Hematopoiesis; Hematopoietic; Hospitalization; Hospitals; Hypertension; IL6 Signaling Pathway; Immune; Immune response; Immune system; Individual; Inflammaging; Inflammatory Response; Integration Host Factors; Intensive Care; Interleukin-1 beta; Interleukin-6; Laboratories; Lead; Leukocytes; Libraries; Location; Measures; Mechanical ventilation; Mediating; Middle East Respiratory Syndrome; Molecular; Mutation; Noise; Outcome; Patients; Persons; Plasma; Precancerous Conditions; Predisposing Factor; Process; RNA; Race; Research; SARS-CoV-2 infection; SARS-CoV-2 positive; Services; Severe Acute Respiratory Syndrome; Signal Transduction; Somatic Mutation; Syndrome; System; Testing; Trans-Omics for Precision Medicine; Troponin; Variant; Virginia; Washington; Work; age related; cardiovascular disorder risk; cohort; cytokine; cytokine release syndrome; electronic data; experimental study; gene cloning; hematopoietic stem cell expansion; individual variation; inflammatory marker; interest; mortality; mutant; myocardial injury; next generation; pathogenic virus; prospective; respiratory; response; severe COVID-19

SUMMARY COVID-19 disease has a diverse range of outcomes, and this individual-to-individual variability is poorly understood. Clonal hematopoiesis is a prevalent, age-associated condition that arises from the accumulation of various somatic mutations in hematopoietic cells and can lead to their clonal amplification. These mutant clones corrupt immune cell function and contribute to mortality and increased cardiovascular disease risk through cytokine dysregulation. The proposed research will investigate the hypothesis that clonal hematopoiesis is a hematologic host factor that predisposes persons to develop severe COVID-19 disease. Through a collaborative effort between Kenneth Walsh Ph.D. (UVA) and Christopher deFilippi M.D. (Inova) the proposed research will explore the possibility that clonal hematopoiesis-mediated alterations to the immune system are associated with clinical laboratory measures of a marked inflammatory response, biochemical evidence of cardiac injury and poor clinical outcomes in patients with COVID-19 infection. Patients will be consented and enrolled at the Inova hospital system in northern Virginia that delivers service to more than 2 million people per year in the Washington, D.C metro area with a large volume of hospitalized COVID-19 positive patients. Upon enrollment, biospecimens will be collected and banked. Clinical data will be extracted from the electronic medical record and stored in research form in Research Electronic Data Capture software. DNA will be sent to Dr. Walsh’s laboratory at UVA for analysis of clonal hematopoiesis. DNA from the Inova group will be processed at UVA to assess clonal hematopoiesis via targeted, error-corrected DNA sequencing. This analysis employs an enrichment panel to capture driver genes of interest and the construction of libraries with DNA barcodes. Following deep next generation DNA sequencing, a bioinformatic platform is employed to distinguish true variant calls from noise at a particular exonic location. These data on clonal hematopoiesis will then be shared with the team at Inova to test whether there are associations between somatic mutations, clinical outcome, and markers of inflammation and cardiac injury.

总结 COVID-19疾病的结局多种多样，这种个体间的差异性很小， 明白克隆性造血是一种普遍的、与年龄相关的疾病，其由以下因素的积累引起： 造血细胞中的各种体细胞突变，并可导致其克隆扩增。这些变异克隆体 破坏免疫细胞功能，导致死亡率和心血管疾病风险增加， 细胞因子失调这项研究将探讨克隆造血是一种 血液宿主因子，使人易患严重COVID-19疾病。通过一个合作 肯尼斯·沃尔什博士(UVA)和克里斯托弗·德菲利皮医学博士（Inova）拟议的研究将 探索克隆造血介导的免疫系统改变与 显著炎症反应的临床实验室测量，心脏损伤的生化证据， COVID-19感染患者的临床结局较差。患者将在Inova获得知情同意并入组 弗吉尼亚州北方的一个医院系统，每年为华盛顿的200多万人提供服务， 华盛顿大都会区有大量住院的COVID-19阳性患者。入组时，生物标本 将被收集并存入银行。临床数据将从电子病历中提取并存储在 研究电子数据采集软件中的研究表格。DNA会被送到弗吉尼亚大学的沃尔什博士的实验室 用于克隆造血的分析。将在UVA下处理Inova组的DNA，以评估克隆 通过有针对性的、错误纠正的DNA测序进行造血。该分析采用富集板， 捕获感兴趣的驱动基因和构建具有DNA条形码的文库。下一篇：Deep Next 在第二代DNA测序中，采用生物信息学平台来区分真正的变异调用与噪音， 特定的外显子位置这些关于克隆造血的数据将与Inova的团队共享， 检测体细胞突变、临床结果和炎症标志物之间是否存在关联 和心脏损伤。