Genetic mechanisms of critical illness in COVID-19

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Pairo-Castineira, Erola, Clohisey, Sara, Klaric, Lucija, Bretherick, Andrew D, Rawlik, Konrad, Pasko, Dorota, Walker, Susan, Parkinson, Nick, Fourman, Max Head, Russell, Clark D et al (show 56 more authors) , Furniss, James, Richmond, Anne, Gountouna, Elvina, Wrobel, Nicola, Harrison, David, Wang, Bo, Wu, Yang, Meynert, Alison, Griffiths, Fiona, Oosthuyzen, Wilna, Kousathanas, Athanasios, Moutsianas, Loukas, Yang, Zhijian, Zhai, Ranran, Zheng, Chenqing, Grimes, Graeme, Beale, Rupert, Millar, Jonathan, Shih, Barbara, Keating, Sean, Zechner, Marie, Haley, Chris, Porteous, David J, Hayward, Caroline, Yang, Jian, Knight, Julian, Summers, Charlotte, Shankar-Hari, Manu, Klenerman, Paul, Turtle, Lance ORCID: 0000-0002-0778-1693, Ho, Antonia, Moore, Shona C ORCID: 0000-0001-8610-2806, Hinds, Charles, Horby, Peter, Nichol, Alistair, Maslove, David, Ling, Lowell, McAuley, Danny, Montgomery, Hugh, Walsh, Timothy, Pereira, Alexandre C, Renieri, Alessandra, Shen, Xia, Ponting, Chris P, Fawkes, Angie, Tenesa, Albert, Caulfield, Mark, Scott, Richard, Rowan, Kathy, Murphy, Lee, Openshaw, Peter JM, Semple, Malcolm G ORCID: 0000-0001-9700-0418, Law, Andrew, Vitart, Veronique, Wilson, James F and Baillie, J Kenneth (2021) Genetic mechanisms of critical illness in COVID-19. NATURE, 591 (7848). 92-+.

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Abstract

Host-mediated lung inflammation is present¹, and drives mortality², in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development³. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10^-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10^-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10^-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10^-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice.

Item Type:	Article
Uncontrolled Keywords:	GenOMICC Investigators, ISARIC4C Investigators, COVID-19 Human Genetics Initiative, 23andMe Investigators, BRACOVID Investigators, Gen-COVID Investigators, Lung, Chromosomes, Human, Pair 12, Chromosomes, Human, Pair 19, Chromosomes, Human, Pair 21, Humans, Critical Illness, Inflammation, 2',5'-Oligoadenylate Synthetase, Critical Care, Multigene Family, Female, Male, TYK2 Kinase, Receptor, Interferon alpha-beta, Receptors, CCR2, Genome-Wide Association Study, Dipeptidyl-Peptidases and Tripeptidyl-Peptidases, Drug Repositioning, United Kingdom, COVID-19
Depositing User:	Symplectic Admin
Date Deposited:	08 Mar 2021 08:10
Last Modified:	18 Jan 2023 23:05
DOI:	10.1038/s41586-020-03065-y
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3112058