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.

Genetic mechanisms of critical illness in COVID-19 / E. Pairo-Castineira, S. Clohisey, L. Klaric, A.D. Bretherick, K. Rawlik, D. Pasko, S. Walker, N. Parkinson, M.H. Fourman, C.D. Russell, J. Furniss, A. Richmond, E. Gountouna, N. Wrobel, D. Harrison, B. Wang, Y. Wu, A. Meynert, F. Griffiths, W. Oosthuyzen, A. Kousathanas, L. Moutsianas, Z. Yang, R. Zhai, C. Zheng, G. Grimes, R. Beale, J. Millar, B. Shih, S. Keating, M. Zechner, C. Haley, D.J. Porteous, C. Hayward, J. Yang, J. Knight, C. Summers, M. Shankar-Hari, P. Klenerman, L. Turtle, A. Ho, S.C. Moore, C. Hinds, P. Horby, A. Nichol, D. Maslove, L. Ling, D. McAuley, H. Montgomery, T. Walsh, A.C. Pereira, A. Renieri, J. Millar, A. Nichol, T. Walsh, M. Shankar-Hari, C. Ponting, J. Meikle, P. Finernan, E. Mcmaster, A. Law, J.K. Baillie, T. Paterson, T. Wackett, R. Armstrong, R. Clark, A. Coutts, L. Donnelly, T. Gilchrist, K. Hafezi, L. Macgillivray, A. Maclean, S. McCafferty, K. Morrice, J. Weaver, C. Boz, A. Golightly, M. Ward, H. 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Genetic mechanisms of critical illness in COVID-19

A. D'Arminio Monforte;S. Rusconi;A. Riva;
2021

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.
2',5'-Oligoadenylate Synthetase; COVID-19; Chromosomes, Human, Pair 12; Chromosomes, Human, Pair 19; Chromosomes, Human, Pair 21; Critical Care; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Drug Repositioning; Female; Genome-Wide Association Study; Humans; Inflammation; Lung; Male; Multigene Family; Receptor, Interferon alpha-beta; Receptors, CCR2; TYK2 Kinase; United Kingdom; Critical Illness
Settore MED/17 - Malattie Infettive
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/861693
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