Host-mediated lung inflammation is present(1), and drives mortality(2), 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(3). 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 x 10(-8)) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 x 10(-8)) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 x 10(-12)) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 x 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.

Pairo-Castineira, E., Clohisey, S., Klaric, L., Bretherick, A.D., Rawlik, K., Pasko, D., et al. (2021). Genetic mechanisms of critical illness in COVID-19. NATURE, 591(7848), 92-98 [10.1038/s41586-020-03065-y].

Genetic mechanisms of critical illness in COVID-19

Renieri;Francesca Mari
Membro del Collaboration Group
;
Sergio Daga
Membro del Collaboration Group
;
Margherita Baldassarri
Membro del Collaboration Group
;
Elisa Benetti
Membro del Collaboration Group
;
Chiara Fallerini
Membro del Collaboration Group
;
Francesca Fava
Membro del Collaboration Group
;
Floriana Valentino
Membro del Collaboration Group
;
Gabriella Doddato
Membro del Collaboration Group
;
Annarita Giliberti
Membro del Collaboration Group
;
Rossella Tita
Membro del Collaboration Group
;
Sara Amitrano
Membro del Collaboration Group
;
Mirella Bruttini
Membro del Collaboration Group
;
Susanna Croci
Membro del Collaboration Group
;
Ilaria Meloni
Membro del Collaboration Group
;
Anna Maria Pinto
Membro del Collaboration Group
;
Elisa Frullanti
Membro del Collaboration Group
;
Maria Antonietta Mencarelli
Membro del Collaboration Group
;
Caterina Lo Rizzo
Membro del Collaboration Group
;
Francesca Montagnani
Membro del Collaboration Group
;
Laura Di Sarno
Membro del Collaboration Group
;
Andrea Tommasi
Membro del Collaboration Group
;
Maria Palmieri
Membro del Collaboration Group
;
Arianna Emiliozzi
Membro del Collaboration Group
;
Massimiliano Fabbiani
Membro del Collaboration Group
;
Barbara Rossetti
Membro del Collaboration Group
;
Giacomo Zanelli
Membro del Collaboration Group
;
Elena Bargagli
Membro del Collaboration Group
;
Laura Bergantini
Membro del Collaboration Group
;
Miriana D'Alessandro
Membro del Collaboration Group
;
Paolo Cameli
Membro del Collaboration Group
;
Federico Anedda
Membro del Collaboration Group
;
Simona Marcantonio
Membro del Collaboration Group
;
Sabino Scolletta
Membro del Collaboration Group
;
Federico Franchi;Maria Antonietta Mazzei
Membro del Collaboration Group
;
Susanna Guerrini
Membro del Collaboration Group
;
Edoardo Conticini
Membro del Collaboration Group
;
Luca Cantarini
Membro del Collaboration Group
;
Bruno Frediani
Membro del Collaboration Group
;
Serafina Valente
Membro del Collaboration Group
;
Marco Mandalà
Membro del Collaboration Group
;
Alessia Giorli
Membro del Collaboration Group
;
Lorenzo Salerni
Membro del Collaboration Group
;
Marco Gori
Membro del Collaboration Group
;
2021-01-01

Abstract

Host-mediated lung inflammation is present(1), and drives mortality(2), 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(3). 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 x 10(-8)) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 x 10(-8)) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 x 10(-12)) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 x 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.
2021
Pairo-Castineira, E., Clohisey, S., Klaric, L., Bretherick, A.D., Rawlik, K., Pasko, D., et al. (2021). Genetic mechanisms of critical illness in COVID-19. NATURE, 591(7848), 92-98 [10.1038/s41586-020-03065-y].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11365/1133625