Genetic mechanisms of critical illness in COVID-19

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) (2021) Genetic mechanisms of critical illness in COVID-19. NATURE, 591 (7848). 92-+.

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Host-mediated lung inflammation is present<sup>1</sup>, and drives mortality<sup>2</sup>, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development<sup>3</sup>. 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<sup>-8</sup>) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10<sup>-8</sup>) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10<sup>-12</sup>) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10<sup>-8</sup>) 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
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