Clonal hematopoiesis and severity of COVID-19 disease

摘要 COVID-19 疾病有多种结果，而且这种个体间差异很小 明白了。克隆性造血是一种普遍存在的、与年龄相关的疾病，是由细胞积累引起的。 造血细胞中的各种体细胞突变可导致其克隆扩增。这些突变克隆 破坏免疫细胞功能，导致死亡并增加心血管疾病风险 细胞因子失调。拟议的研究将调查克隆造血是一种假设 使人容易患上严重的 COVID-19 疾病的血液宿主因素。通过协作 肯尼斯·沃尔什博士之间的努力(UVA) 和 Christopher deFilippi M.D. (Inova) 拟议的研究将 探索克隆造血介导的免疫系统改变与以下因素相关的可能性： 显着炎症反应的临床实验室测量、心脏损伤的生化证据和 COVID-19 感染患者的临床结果不佳。患者将获得 Inova 同意并登记 弗吉尼亚州北部的医院系统每年为华盛顿超过 200 万人提供服务， 华盛顿都会区有大量住院的 COVID-19 阳性患者。登记后，生物样本 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 研究电子数据捕获软件中的研究形式。 DNA 将被送往 Walsh 博士在 UVA 的实验室 用于克隆造血分析。来自 Inova 集团的 DNA 将在 UVA 进行处理以评估克隆 通过有针对性的、纠错的 DNA 测序进行造血。该分析采用富集面板来 捕获感兴趣的驱动基因并使用 DNA 条形码构建文库。接下来深入 一代 DNA 测序，生物信息平台用于区分真正的变异调用和噪音 特定的外显子位置。这些有关克隆造血的数据随后将与 Inova 团队共享，以 测试体细胞突变、临床结果和炎症标志物之间是否存在关联 和心脏损伤。

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.