Role of host genetics in COVID-19 susceptibility and severity of infection

新型冠状病毒2019 SARS-CoV-2（COVID-19）感染是一种全球流行性疾病，严重影响了美国。新出现的数据表明，种族和少数民族群体受到COVID-19的影响不成比例，非裔美国人（AA）在住院患者中的比例过高。临床症状从大约80%的病例中的轻度到危重不等。确定的风险因素是年龄，性别和几种合并症，包括癌症。临床严重程度的许多其他因素仍然无法解释。该提案将利用Quest Diagnostics实验室经实验室证实的COVID-19阳性个体的残留生物标本来研究COVID-19的宿主遗传学。Quest Diagnostics是一家国家商业实验室，迄今已进行了超过375万次COVID-19检测，并确定了超过298，000例阳性病例。我们预计将包括>7500个与NCI内部合作进行全基因组基因分型的样本。虽然没有确定的严重性预测因子，但已观察到来自总血细胞计数的某些生物标志物与更差的结局相关。一些研究报道了不受控制的细胞因子释放的作用与不良结局相关。我们将结合生物标志物，如淋巴细胞计数，中性粒细胞计数和其他炎症标志物，以制定严重程度评分。使用这个严重程度评分，我们将个人分为轻度，严重或严重感染。将利用来自Quest的去识别临床数据和来自国家死亡指数的生命状态数据的生物标本，在检测呈阳性后的28天内确定宿主遗传因素是否会改变COVID-19的结果。我们将发现新的遗传变异和克隆造血（CH）与感染的严重程度，死亡率和细胞因子风暴。最后，我们将在来自MSKCC的2，000名个体的癌症队列中比较这些新型遗传生物标志物，以对比COVID-19在癌症护理中的具体结果。这项研究代表了遗传关联研究中最大的COVID-19队列之一。这些数据将用于比较遗传多样性及其在COVID-19严重程度中的作用，并将增加对宿主对轻度和重度病毒感染和炎症的免疫反应的组成决定因素的理解。

Novel Coronavirus 2019 SARS-CoV-2 (COVID-19) infection is a global pandemic disease that has severely affected the United States. Emerging data suggests that racial and ethnic minority groups are disproportionately affected by COVID-19 and African Americans (AA) are overrepresented among hospitalized patients. The clinical symptoms vary from mild in approximately 80% of cases to critically ill. Established risk factors are age, gender and several comorbidities including cancer. Many other factors in clinical severity remain unexplained. This proposal will leverage remnant biospecimens from laboratory-proven COVID-19 positive individuals at Quest Diagnostics, a national commercial laboratory that has performed over 3.75 million COVID-19 tests and has identified over 298,000 positive cases to date, to study host-genetics of COVID19. We expect to include >7500 samples with whole genome genotyping, performed in collaboration with intramural NCI. While there are no established predictors of severity, certain biomarkers from total blood count have been observed to correlate with worse outcomes. Several studies have reported the role of uncontrolled cytokine release to be correlated with poor outcome. We will incorporate biomarkers such as lymphocyte count, neutrophil count and other inflammation markers to develop a severity score. Using this severity score, we will classify individuals as having mild, severe or critical infection. Biospecimens with de-identified clinical data from Quest and vital status data from the National Death Index in the 28 days period from testing positive, will be utilized to determine whether host genetic factors modify COVID-19 outcomes. We will discover novel genetic variation and clonal hematopoiesis (CH) associated with infection severity, mortality and cytokine storm. Finally, we will compare these novel genetic biomarkers in a cancer cohort of 2,000 individuals from MSKCC to contrast COVID-19 specific outcomes in cancer care. This study represents one of the largest COVID-19 cohorts for genetic association studies. These data will be used to compare genetic diversity and the role it plays in COVID-19 severity and will add to the understanding of constitutional determinants of host immune response to mild and severe viral infection and inflammation.