Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.
Eur J Hum Genet. 2021 Aug;29(8):1312-1315. doi: 10.1038/s41431-021-00886-x. Epub 2021 Apr 19.
Critically ill coronavirus disease 2019 (COVID-19) is characterized by severe cytokine storms, a hyperinflammatory condition intimately related to the development of fatal outcomes. Why some individuals seem particularly vulnerable to severe cytokine storms is still unknown. Primary immunodeficiency (PID)-related genes are inherited factors that dysregulate host inflammatory responses to infection, especially hemophagocytic lymphohistiocytosis (HLH)-related genes, established as contributors to the development of excessive cytokine storms. We analyzed the association between PID gene variants with severe cytokine storms in COVID-19. We conducted whole-exome sequencing in 233 hospitalized COVID-19 patients and identified four PID gene (UNC13D, AP3B1, RNF168, DHX58) variants were significantly enriched in COVID-19 patients experiencing severe cytokine storms. The total percentage of COVID-19 patients with variants in UNC13D or AP3B1, two typical HLH genes, was dramatically higher in high-level cytokine group than in low-level group (33.3 vs. 5.7%, P < 0.001). Germline variants in UNC13D and AP3B1 were associated with the development of severe cytokine storms, fatal outcomes in COVID-19. These findings advance the understanding of individual susceptibility to severe cytokine storms and help optimize the current management of COVID-19.
严重的 2019 冠状病毒病（COVID-19）的特点是严重的细胞因子风暴，这是一种与致命结局发展密切相关的过度炎症状态。为什么有些人似乎特别容易受到严重的细胞因子风暴的影响，目前仍不清楚。原发性免疫缺陷（PID）相关基因是失调宿主对感染的炎症反应的遗传因素，特别是噬血细胞性淋巴组织细胞增生症（HLH）相关基因，被认为是导致过度细胞因子风暴发展的因素。我们分析了 PID 基因变异与 COVID-19 中严重细胞因子风暴之间的关系。我们对 233 名住院 COVID-19 患者进行了全外显子组测序，发现四个 PID 基因（UNC13D、AP3B1、RNF168、DHX58）的变异在经历严重细胞因子风暴的 COVID-19 患者中明显富集。UNC13D 或 AP3B1（两个典型的 HLH 基因）的变异在高水平细胞因子组中的 COVID-19 患者中的总百分比明显高于低水平组（33.3%比 5.7%，P<0.001）。UNC13D 和 AP3B1 种系变异与 COVID-19 中严重细胞因子风暴和致命结局的发生有关。这些发现加深了对个体易患严重细胞因子风暴的理解，并有助于优化 COVID-19 的当前管理。
