Centre for Individualised Infection Medicine, CiiM, a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany.
TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany.
Front Immunol. 2022 May 12;13:859387. doi: 10.3389/fimmu.2022.859387. eCollection 2022.
Recent genome-wide association studies (GWASs) of COVID-19 patients of European ancestry have identified genetic loci significantly associated with disease severity. Here, we employed the detailed clinical, immunological and multi-omics dataset of the Human Functional Genomics Project (HFGP) to explore the physiological significance of the host genetic variants that influence susceptibility to severe COVID-19. A genomics investigation intersected with functional characterization of individuals with high genetic risk for severe COVID-19 susceptibility identified several major patterns: i. a large impact of genetically determined innate immune responses in COVID-19, with ii. increased susceptibility for severe disease in individuals with defective cytokine production; iii. genetic susceptibility related to ABO blood groups is probably mediated through the von Willebrand factor (VWF) and endothelial dysfunction. We further validated these identified associations at transcript and protein levels by using independent disease cohorts. These insights allow a physiological understanding of genetic susceptibility to severe COVID-19, and indicate pathways that could be targeted for prevention and therapy.
最近针对欧洲血统 COVID-19 患者的全基因组关联研究（GWAS）已经确定了与疾病严重程度显著相关的遗传位点。在这里，我们利用人类功能基因组学计划（HFGP）详细的临床、免疫学和多组学数据集，探索影响严重 COVID-19 易感性的宿主遗传变异的生理意义。对具有严重 COVID-19 易感性高遗传风险的个体进行基因组学研究与功能特征分析，确定了几种主要模式：i. 遗传决定的先天免疫反应对 COVID-19 的影响很大，ii. 细胞因子产生缺陷的个体易患严重疾病；iii. 与 ABO 血型相关的遗传易感性可能是通过血管性血友病因子（VWF）和内皮功能障碍介导的。我们通过使用独立的疾病队列，在转录和蛋白水平上进一步验证了这些关联。这些发现为严重 COVID-19 的遗传易感性提供了生理学理解，并指出了可能用于预防和治疗的途径。
