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

宿主遗传学在 COVID-19 易感性和感染严重程度中的作用

• 批准号: 10201314
• 负责人: CRAIG B THOMPSON
• 金额: $ 17.7万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10201314
• 关键词: 2019-nCoV; Affect; African American; Age Factors; American; Antibodies; Biological; Biological Markers; Blood; COVID-19; Cancer Patient; Cardiovascular Diseases; Cells; Cessation of life; Chronic; Clinical; Clinical Data; Collaborations; Constitutional; Critical Illness; DNA; Data; Databases; Derivation procedure; Diagnosis; Diagnostic; Disease; Division of Cancer Epidemiology and Genetics; Ensure; Funding; Future; Gender; Genetic; Genetic Markers; Genetic Predisposition to Disease; Genetic Variation; Genomics; Genotype; Haplotypes; Hematopoiesis; Heritability; Hospitalization; Immune response; Immune system; Immunologic Tests; Individual; Infection; Inflammation; Inflammatory; Infrastructure; Institutional Review Boards; Laboratories; Lymphocyte Count; Malignant Neoplasms; Mediator of activation protein; Medical Genetics; Memorial Sloan-Kettering Cancer Center; Metabolic; Minority Groups; Mutation; National Human Genome Research Institute; New York; Oral; Outcome; Pathway interactions; Patients; Play; Predisposition; Protocols documentation; Reporting; Research; Reverse Transcriptase Polymerase Chain Reaction; Risk; Risk Factors; Role; SNP array; SNP genotyping; Sample Size; Sampling; Severities; Severity of illness; Somatic Mutation; Statistical Methods; Stratification; Swab; Symptoms; Testing; Therapeutic; United States; United States National Institutes of Health; Variant; Virus Diseases; Vital Status; age related; cancer care; cohort; comorbidity; coronavirus disease; cytokine; cytokine release syndrome; ethnic minority population; genetic association; genetic epidemiology; genetic variant; genome wide association study; genomic data; indexing; inflammatory marker; insight; mortality; neutrophil; novel; pandemic disease; polygenic risk score; prospective; racial minority; whole genome

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.

新型冠状病毒2019 SARS-CoV-2(新冠肺炎)感染是一种全球大流行疾病，已严重影响美国。新出现的数据表明，种族和少数民族群体受到新冠肺炎的影响不成比例，非洲裔美国人(AA)在住院患者中的比例过高。临床症状从大约80%的轻微病例到危重病例不等。确定的风险因素是年龄、性别和包括癌症在内的几种共病。临床严重程度的许多其他因素仍未得到解释。这项建议将利用Quest Diagnostics实验室证实的新冠肺炎阳性个体的残留生物检疫菌来研究CoVID19的宿主遗传学。Quest Diagnostics是一家国家商业实验室，已进行了375万多次新冠肺炎检测，迄今已确定298,000多例阳性病例。我们预计将包括与NCI合作进行全基因组基因分型的7500个样本。虽然目前还没有确定的严重程度的预测因素，但已经观察到总血细胞计数的某些生物标志物与更差的结果相关。一些研究已经报道，不受控制的细胞因子释放的作用与不良结局相关。我们将结合淋巴细胞计数、中性粒细胞计数和其他炎症标志物等生物标志物来制定严重程度评分。使用这一严重程度评分，我们将把个人分为轻度感染、严重感染或严重感染。从检测呈阳性开始的28天内，带有Quest的未识别临床数据和国家死亡指数的生命状态数据的生物标记物将被用于确定宿主遗传因素是否影响新冠肺炎的结果。我们将发现新的遗传变异和克隆性造血(CH)与感染严重程度、死亡率和细胞因子风暴相关。最后，我们将在MSKCC的2,000名患者的癌症队列中比较这些新的遗传生物标记物，以对比新冠肺炎在癌症治疗中的特定结果。这项研究代表了新冠肺炎基因关联研究中最大的队列之一。这些数据将被用来比较遗传多样性及其在新冠肺炎严重程度中所起的作用，并将有助于理解宿主对轻度和严重病毒感染和炎症的免疫反应的构成决定因素。