A proteome-wide genetic investigation identifies several SARS-CoV-2-exploited host targets of clinical relevance
Year: 2021
Type: article
Abstract: The virus SARS-CoV-2 can exploit biological vulnerabilities in susceptible hosts that predispose to development of severe COVID-19. Previous reports have identified several host proteins related to the interferon response (e.g. OAS1), interleukin-6 signalling (IL-6R), and the coagulation cascade (linked via ABO) that were associated with risk of COVID-19. In the present study, we performed proteome-wide genetic colocalisation tests leveraging publicly available protein and COVID-19 datasets, to identify additional proteins that may contribute to COVID-19 risk. Our analytic approach identified several known targets (e.g. ABO, OAS1), but also nominated new proteins such as soluble FAS (colocalisation probability > 0.9, p = 1 × 10 −4 ), implicating FAS-mediated apoptosis as a potential target for COVID-19 risk. We also undertook polygenic (pan) and cis-Mendelian randomisation analyses that showed consistent associations of genetically predicted ABO protein with several COVID-19 phenotypes. The ABO signal was associated with plasma concentrations of several proteins, with the strongest association observed with CD209 in several proteomic datasets. We demonstrated experimentally that CD209 directly interacts with the spike protein of SARS-CoV-2, suggesting a mechanism that could explain the ABO association with COVID-19. Our work provides a prioritised list of host targets potentially exploited by SARS-CoV-2 and is a precursor for further research on CD209 and FAS as therapeutically tractable targets for COVID-19.
Source: eLife
DOI: 10.7554/elife.69719
Authors: Mohd A Karim, Jarrod Shilts, Jeremy Schwartzentruber, James Hayhurst, Annalisa Buniello, Elmutaz Shaikho Elhaj Mohammed, Jie Zheng, Michael V Holmes, David Ochoa, Miguel Carmona, Joseph Maranville, Tom R. Gaunt, Valur Emilsson, Vilmundur Gudnason, Ellen M. McDonagh, Gavin J. Wright, Maya Ghoussaini, Ian Dunham
Institutions: Wellcome Sanger Institute, Open Targets, European Bioinformatics Institute, Bristol-Myers Squibb (United States), The University of Texas Southwestern Medical Center, University of Bristol, MRC Integrative Epidemiology Unit, Medical Research Council, University of Oxford, MRC Population Health Research Unit, University of Iceland, Icelandic Heart Association, University of York, Hull York Medical School
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,500
OpenAlex ID: W3196067893