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

SARS-CoV-2 （COVID-19）感染是一种全球大流行疾病，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，非裔美国人在住院患者中的比例过高。临床症状从约80%的病例的轻度到危重不等。确定的危险因素是年龄、性别和包括癌症在内的几种合并症。临床严重程度的许多其他因素仍未得到解释。该提案将利用Quest Diagnostics实验室证实的COVID-19阳性个体的剩余生物标本来研究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375万多次COVID-19检测，并确定了29.8万多例阳性病例。我们预计将包括与校内NCI合作进行的bb0 7500个全基因组基因分型样本。虽然没有确定的严重程度的预测因素，但已经观察到来自总血细胞计数的某些生物标志物与较差的结果相关。一些研究报道了不受控制的细胞因子释放与不良预后相关的作用。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来制定严重程度评分。使用这个严重程度评分，我们将个人分为轻度、严重或危重感染。将利用来自Quest的去识别临床数据和来自国家死亡指数的28天内生命状态数据的生物标本，确定宿主遗传因素是否会改变COVID-19的结局。我们将发现与感染严重程度、死亡率和细胞因子风暴相关的新的遗传变异和克隆造血（CH）。最后，我们将在2000名来自MSKCC的癌症队列中比较这些新的遗传生物标志物，以对比2019冠状病毒病在癌症治疗中的特异性结果。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，并将增进对宿主对轻度和重度病毒感染和炎症免疫反应的体质决定因素的理解。

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.