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 MariMembro del Collaboration Group
;Sergio DagaMembro del Collaboration Group
;Margherita BaldassarriMembro del Collaboration Group
;Elisa BenettiMembro del Collaboration Group
;Chiara FalleriniMembro del Collaboration Group
;Francesca FavaMembro del Collaboration Group
;Floriana ValentinoMembro del Collaboration Group
;Gabriella DoddatoMembro del Collaboration Group
;Annarita GilibertiMembro del Collaboration Group
;Rossella TitaMembro del Collaboration Group
;Sara AmitranoMembro del Collaboration Group
;Mirella BruttiniMembro del Collaboration Group
;Susanna CrociMembro del Collaboration Group
;Ilaria MeloniMembro del Collaboration Group
;Anna Maria PintoMembro del Collaboration Group
;Elisa FrullantiMembro del Collaboration Group
;Maria Antonietta MencarelliMembro del Collaboration Group
;Caterina Lo RizzoMembro del Collaboration Group
;Francesca MontagnaniMembro del Collaboration Group
;Laura Di SarnoMembro del Collaboration Group
;Andrea TommasiMembro del Collaboration Group
;Maria PalmieriMembro del Collaboration Group
;Arianna EmiliozziMembro del Collaboration Group
;Massimiliano FabbianiMembro del Collaboration Group
;Barbara RossettiMembro del Collaboration Group
;Giacomo ZanelliMembro del Collaboration Group
;Elena BargagliMembro del Collaboration Group
;Laura BergantiniMembro del Collaboration Group
;Miriana D'AlessandroMembro del Collaboration Group
;Paolo CameliMembro del Collaboration Group
;Federico AneddaMembro del Collaboration Group
;Simona MarcantonioMembro del Collaboration Group
;Sabino ScollettaMembro del Collaboration Group
;Federico Franchi;Maria Antonietta MazzeiMembro del Collaboration Group
;Susanna GuerriniMembro del Collaboration Group
;Edoardo ConticiniMembro del Collaboration Group
;Luca CantariniMembro del Collaboration Group
;Bruno FredianiMembro del Collaboration Group
;Serafina ValenteMembro del Collaboration Group
;Marco MandalàMembro del Collaboration Group
;Alessia GiorliMembro del Collaboration Group
;Lorenzo SalerniMembro del Collaboration Group
;Marco GoriMembro 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.File | Dimensione | Formato | |
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https://hdl.handle.net/11365/1133625