Clonal hematopoiesis and severity of COVID-19 disease

摘要 新冠肺炎病的预后多种多样，这种个体间的可变性很差 明白了。克隆性造血是一种流行的与年龄相关的疾病，由 造血细胞中的各种体细胞突变，并可导致其克隆性扩增。这些突变克隆 通过以下途径破坏免疫细胞功能并导致死亡和心血管疾病风险增加 细胞因子失调。这项拟议的研究将调查克隆造血是一种 易患严重新冠肺炎病的血液宿主因素。通过协作 肯尼斯·沃尔什博士(UVA)和克里斯托弗·德利皮(Christopher Defilippi)医学博士(Inova)共同努力，拟议的研究将 探讨克隆性造血介导的免疫系统改变与 临床实验室检测有明显的炎症反应，心脏损伤的生化证据和 新冠肺炎感染患者的临床转归较差。患者将被同意并在Inova登记 弗吉尼亚州北部每年为华盛顿州200多万人提供服务的医院系统， 华盛顿特区都会区有大量住院的新冠肺炎阳性患者。在注册时，生物制品 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将被送到沃尔什博士在弗吉尼亚大学的实验室 用于克隆性造血分析。来自Inova团队的DNA将在UVA进行处理，以评估克隆 通过定向、纠错的DNA测序进行造血。这项分析使用了一个浓缩小组来 捕获感兴趣的驱动基因并用DNA条形码构建文库。紧随其后的是 代DNA测序，一个生物信息学平台被用来区分真正的变异叫声和噪音 一个特殊的外显子位置。然后，这些关于克隆造血的数据将与Inova的团队共享到 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。

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.