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Genetic Predisposition to Elevated Levels of Circulating ADAM17 Is Associated with the Risk of Severe COVID-19

Pan, Mengyu LU orcid ; Goncalves, Isabel LU orcid ; Edsfeldt, Andreas LU ; Sun, Jiangming LU orcid and Swärd, Per LU (2023) In International Journal of Molecular Sciences 24(21).
Abstract

High levels of ADAM17 activity have emerged as an important mediator in severe COVID-19. This study aims to characterize eventual causal relationships between ADAM17 and COVID-19. Using Mendelian randomization analyses, we examined the causal effects of circulating ADAM17 on COVID-19 outcomes using summary statistics from large, genome-wide association studies of ADAM17 (up to 35,559 individuals) from the Icelandic Cancer Project and deCODE genetics, as well as critically ill COVID-19 patients (cases: 13,769; controls: 1,072,442), hospitalized COVID-19 patients (cases: 32,519; controls: 2,062,805) and reported SARS-CoV-2 infections (cases: 122,616; controls: 2,475,240) from the COVID-19 Host Genetics Initiative. The Mendelian... (More)

High levels of ADAM17 activity have emerged as an important mediator in severe COVID-19. This study aims to characterize eventual causal relationships between ADAM17 and COVID-19. Using Mendelian randomization analyses, we examined the causal effects of circulating ADAM17 on COVID-19 outcomes using summary statistics from large, genome-wide association studies of ADAM17 (up to 35,559 individuals) from the Icelandic Cancer Project and deCODE genetics, as well as critically ill COVID-19 patients (cases: 13,769; controls: 1,072,442), hospitalized COVID-19 patients (cases: 32,519; controls: 2,062,805) and reported SARS-CoV-2 infections (cases: 122,616; controls: 2,475,240) from the COVID-19 Host Genetics Initiative. The Mendelian randomization (MR) analyses demonstrated that a 1 standard deviation increase in genetically determined circulating ADAM17 (extracellular domain) was associated with an increased risk of developing critical ill COVID-19 (odds ratio [OR] = 1.26, 95% confidence interval [CI]:1.03–1.55). The multivariable MR analysis suggested a direct causal role of circulating ADAM17 (extracellular domain) in the risk of developing critical COVID-19 (OR = 1.09; 95% CI:1.01–1.17) when accounting for body mass index. No causal effect for the cytoplasmic domain of ADAM17 on COVID-19 was observed. Our results suggest that an increased genetic susceptibility to elevated levels of circulating ADAM17 (extracellular domain) is associated with a higher risk of suffering from severe COVID-19, strengthening the idea that the timely selective inhibition of ADAM17 could be a potential therapeutic target worthy of investigation.

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author
; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
ADAM17, causality association, COVID-19 severity, extracellular, genome-wide association study, Mendelian randomization
in
International Journal of Molecular Sciences
volume
24
issue
21
article number
15879
publisher
MDPI AG
external identifiers
  • pmid:37958866
  • scopus:85176339358
ISSN
1661-6596
DOI
10.3390/ijms242115879
language
English
LU publication?
yes
additional info
Funding Information: This work was supported by grants from the Kockska Foundation, ALF Grants Region Skåne, the Bo & Kerstin Hjelt Diabetes Foundation, Swedish Stroke Association, Söderström König Foundation (SLS-969070), the Swedish Research Council (2019-01260), the Swedish Heart and Lung Foundation (20220284, 20200403), Skåne University Hospital funds, Swedish Stroke Association, Albert Påhlssons Foundation and Lund University Diabetes Center (Swedish Research Council—Strategic Research Area Exodiab Dnr 2009–1039, Linnaeus grant Dnr 349-2006-23 and the Swedish Foundation for Strategic Research Dnr IRC15-006). Publisher Copyright: © 2023 by the authors.
id
2a9d9113-dcb4-4c54-97a8-8c2eb18768ac
date added to LUP
2024-01-05 07:52:52
date last changed
2024-04-20 04:15:29
@article{2a9d9113-dcb4-4c54-97a8-8c2eb18768ac,
  abstract     = {{<p>High levels of ADAM17 activity have emerged as an important mediator in severe COVID-19. This study aims to characterize eventual causal relationships between ADAM17 and COVID-19. Using Mendelian randomization analyses, we examined the causal effects of circulating ADAM17 on COVID-19 outcomes using summary statistics from large, genome-wide association studies of ADAM17 (up to 35,559 individuals) from the Icelandic Cancer Project and deCODE genetics, as well as critically ill COVID-19 patients (cases: 13,769; controls: 1,072,442), hospitalized COVID-19 patients (cases: 32,519; controls: 2,062,805) and reported SARS-CoV-2 infections (cases: 122,616; controls: 2,475,240) from the COVID-19 Host Genetics Initiative. The Mendelian randomization (MR) analyses demonstrated that a 1 standard deviation increase in genetically determined circulating ADAM17 (extracellular domain) was associated with an increased risk of developing critical ill COVID-19 (odds ratio [OR] = 1.26, 95% confidence interval [CI]:1.03–1.55). The multivariable MR analysis suggested a direct causal role of circulating ADAM17 (extracellular domain) in the risk of developing critical COVID-19 (OR = 1.09; 95% CI:1.01–1.17) when accounting for body mass index. No causal effect for the cytoplasmic domain of ADAM17 on COVID-19 was observed. Our results suggest that an increased genetic susceptibility to elevated levels of circulating ADAM17 (extracellular domain) is associated with a higher risk of suffering from severe COVID-19, strengthening the idea that the timely selective inhibition of ADAM17 could be a potential therapeutic target worthy of investigation.</p>}},
  author       = {{Pan, Mengyu and Goncalves, Isabel and Edsfeldt, Andreas and Sun, Jiangming and Swärd, Per}},
  issn         = {{1661-6596}},
  keywords     = {{ADAM17; causality association; COVID-19 severity; extracellular; genome-wide association study; Mendelian randomization}},
  language     = {{eng}},
  number       = {{21}},
  publisher    = {{MDPI AG}},
  series       = {{International Journal of Molecular Sciences}},
  title        = {{Genetic Predisposition to Elevated Levels of Circulating ADAM17 Is Associated with the Risk of Severe COVID-19}},
  url          = {{http://dx.doi.org/10.3390/ijms242115879}},
  doi          = {{10.3390/ijms242115879}},
  volume       = {{24}},
  year         = {{2023}},
}