Germline variants in UNC13D and AP3B1 are enriched in COVID-19 patients experiencing severe cytokine storms.

Abstract

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.

• Authors: Hui Luo, Dan Liu, Wenbing Liu, Gaoxiang Wang, Liting Chen, Yang Cao, Jia Wei, Min Xiao, Xin Liu, Gang Huang, Wei Wang, Jianfeng Zhou, Qian-Fei Wang
• Journal: European journal of human genetics : EJHG (Eur J Hum Genet) Vol. 29 Issue 8 Pg. 1312-1315 (08 2021) ISSN: 1476-5438 [Electronic] England
• PMID: 33867526 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The Author(s).

Chemical References

• AP3B1 protein, human
• Adaptor Protein Complex 3
• Adaptor Protein Complex beta Subunits
• Membrane Proteins
• UNC13D protein, human

Topics

• Adaptor Protein Complex 3 (genetics, metabolism)
• Adaptor Protein Complex beta Subunits (genetics, metabolism)
• Aged
• COVID-19 (genetics, immunology, metabolism, pathology)
• Cytokine Release Syndrome (genetics)
• Humans
• Lymphohistiocytosis, Hemophagocytic (genetics)
• Membrane Proteins (genetics, metabolism)
• Middle Aged