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

总结 人类白细胞位于人类主要组织相容性复合体（MHC）染色体6p 21内， 抗原（HLA）区是人类基因组中最重要的医学区域。HLA区域的变异 它与150多种疾病和病症有关，包括传染病、癌症和重大疾病。 药物过敏虽然目前对宿主遗传因素在COVID-19中的影响知之甚少， 迄今为止的流行病学显示，在确诊的感染病例中， 这似乎不能用已知的风险因素来解释。由于它在免疫反应中的关键作用 了解HLA变异的作用有望为理解人类免疫缺陷提供重要的见解。 COVID-19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 具体目标1，我们将利用现有的数据资源，与国家骨髓捐献者计划合作， 和DKMS登记处收集有关COVID-19症状，测试和结果的数据，使用一种新的，经过验证的 智能手机应用程序在一个非常大的样本（N= 300，000 - 500，000）的志愿者骨髓供体与预先存在 HLA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效的检查。 在《特定目标2》中，我们将采用一种新的、经过验证的方法对扩展的MHC进行下一代测序。 （~ 5 Mb），包括所有经典和非经典HLA基因座，以及超过150个额外的免疫系统基因座， 大量不同的COVID-19患者队列（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置于背景中 通过检测SARS-CoV-2抗原的HLA呈递作用。总之，我们将利用 大型和多样化的患者队列以及尖端技术和分子生物学，以揭示 这些重要的免疫位点。

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.