MHC Variation in Host Response to SARS-CoV2 and COVID-19 Outcomes

摘要 人类白细胞位于人类主要组织相容性复合体(MHC)染色体6p21内 抗原(HLA)区是人类基因组中最重要的医学区域。人类白细胞抗原区域的变异 与150多种疾病和状况有关，包括传染病、癌症和重大 药物过敏症。虽然目前对COVID-19宿主遗传因素的影响知之甚少， 到目前为止，流行病学显示，在确诊的感染病例中，病程差异很大。 似乎不能完全用已知的风险因素来解释。因为它在免疫反应中起着关键作用 理解人类白细胞抗原变异的作用有望提供与理解 新冠肺炎的免疫发病机制，同时为疫苗开发和潜在的免疫疗法提供信息。在……里面 具体目标1，我们将利用现有的数据资源，与国家骨髓捐赠者计划合作 和DKMS登记处使用一种新的、经过验证的 在一个非常大的样本(N=300,000-500,000)中使用智能手机应用程序，这些志愿者的骨髓捐赠者 人类白细胞抗原基因分型数据，允许对这些基因在疾病中的作用进行非常有力的检查。 在具体目标2中，我们将使用一种新的、经过验证的方法来对扩展的MHC进行下一代测序 (~5Mb)，包括所有经典和非经典人类白细胞抗原基因座，以及超过150个额外的免疫系统基因座，在 新冠肺炎患者的大而多样的队列(N=2000)，以及具有纵向临床数据的患者队列 和广泛的免疫分析(N=300)。最后，在具体目标3中，我们将把这些关联研究联系起来 通过检测SARS-CoV-2抗原的人类白细胞抗原提呈作用。总而言之，我们将利用 大量和多样化的患者队列与尖端技术和分子生物学一起揭示 新冠肺炎中的这些重要免疫位点。

SUMMARY Located within the human Major Histocompatibility Complex (MHC) chromosome 6p21, the Human Leukocyte Antigen (HLA) region is the most medically important region of the human genome. Variation in the HLA region has been associated with over 150 diseases and conditions, including infectious disease, cancers, and major drug-hypersensitivities. While little is known at this point about the impact of host genetic factors in COVID-19, the epidemiology to-date reveals wide variation in disease course among confirmed cases of infection that does not appear to be fully explained by known risk factors. Because of its pivotal role in the immune response understanding the role of HLA variation promises to provide important insights relevant to understanding the immunopathogenesis of COVID-19, while informing vaccine development and potential immunotherapies. In Specific Aim 1, we will exploit an existing data resource, partnering with the National Marrow Donor Program and DKMS registries to collect data on COVID-19 symptoms, testing and outcomes using a novel, validated smartphone app in a very large sample (N=300,000-500,000) of volunteer bone marrow donors with pre-existing HLA genotyping data, allowing an extraordinarily well-powered examination of the role of these genes in disease. In Specific Aim 2, we will employ a novel, validated method for next-generation sequencing of the extended MHC (~5Mb), including all classical and non-classical HLA loci, as well as over 150 additional immune system loci, in large and diverse cohorts of COVID-19 patients (N=2000), as well patient cohorts with longitudinal clinical data and extensive immunoprofiling (N=300). Finally, in Specific Aim 3 we will contextualize these association studies through examination of the role of HLA presentation of SARS-CoV-2 antigens. In summary, we will leverage large and diverse patient cohorts alongside cutting edge technology and molecular biology to reveal the role of these important immune loci in COVID-19.