Genetic mechanisms of critical illness in COVID-19.

Autor: Pairo-Castineira E; Roslin Institute, University of Edinburgh, Edinburgh, UK.; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK., Clohisey S; Roslin Institute, University of Edinburgh, Edinburgh, UK., Klaric L; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK., Bretherick AD; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK., Rawlik K; Roslin Institute, University of Edinburgh, Edinburgh, UK., Pasko D; Genomics England, London, UK., Walker S; Genomics England, London, UK., Parkinson N; Roslin Institute, University of Edinburgh, Edinburgh, UK., Fourman MH; Roslin Institute, University of Edinburgh, Edinburgh, UK., Russell CD; Roslin Institute, University of Edinburgh, Edinburgh, UK.; Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK., Furniss J; Roslin Institute, University of Edinburgh, Edinburgh, UK., Richmond A; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK., Gountouna E; Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK., Wrobel N; Edinburgh Clinical Research Facility, Western General Hospital, University of Edinburgh, Edinburgh, UK., Harrison D; Intensive Care National Audit & Research Centre, London, UK., Wang B; Roslin Institute, University of Edinburgh, Edinburgh, UK., Wu Y; Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia., Meynert A; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK., Griffiths F; Roslin Institute, University of Edinburgh, Edinburgh, UK., Oosthuyzen W; Roslin Institute, University of Edinburgh, Edinburgh, UK., Kousathanas A; Genomics England, London, UK., Moutsianas L; Genomics England, London, UK., Yang Z; Biostatistics Group, School of Life Sciences, Sun Yat-sen University, Guangzhou, China., Zhai R; Biostatistics Group, School of Life Sciences, Sun Yat-sen University, Guangzhou, China., Zheng C; Biostatistics Group, School of Life Sciences, Sun Yat-sen University, Guangzhou, China., Grimes G; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK., Beale R; The Crick Institute, London, UK., Millar J; Roslin Institute, University of Edinburgh, Edinburgh, UK., Shih B; Roslin Institute, University of Edinburgh, Edinburgh, UK., Keating S; Intensive Care Unit, Royal Infirmary of Edinburgh, Edinburgh, UK., Zechner M; Roslin Institute, University of Edinburgh, Edinburgh, UK., Haley C; Roslin Institute, University of Edinburgh, Edinburgh, UK., Porteous DJ; Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK., Hayward C; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK.; Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK., Yang J; School of Life Sciences, Westlake University, Hangzhou, China.; Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China., Knight J; Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK., Summers C; Department of Medicine, University of Cambridge, Cambridge, UK., Shankar-Hari M; Department of Intensive Care Medicine, Guy's and St Thomas' NHS Foundation Trust, London, UK.; School of Immunology and Microbial Sciences, King's College London, London, UK., Klenerman P; Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK., Turtle L; NIHR Health Protection Research Unit for Emerging and Zoonotic Infections, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK., Ho A; MRC-University of Glasgow Centre for Virus Research, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK., Moore SC; NIHR Health Protection Research Unit for Emerging and Zoonotic Infections, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK., Hinds C; William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK., Horby P; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK., Nichol A; Clinical Research Centre at St Vincent's University Hospital, University College Dublin, Dublin, Ireland.; Australian and New Zealand Intensive Care Research Centre, Monash University, Melbourne, Victoria, Australia.; Intensive Care Unit, Alfred Hospital, Melbourne, Victoria, Australia., Maslove D; Department of Critical Care Medicine, Queen's University and Kingston Health Sciences Centre, Kingston, Ontario, Canada., Ling L; Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China., McAuley D; Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast, UK.; Department of Intensive Care Medicine, Royal Victoria Hospital, Belfast, UK., Montgomery H; UCL Centre for Human Health and Performance, University College London, London, UK., Walsh T; Intensive Care Unit, Royal Infirmary of Edinburgh, Edinburgh, UK., Pereira AC; Faculty of Medicine, University of São Paulo, São Paulo, Brazil.; Heart Institute, University of São Paulo, São Paulo, Brazil., Renieri A; Medical Genetics, University of Siena, Siena, Italy.; Genetica Medica, Azienda Ospedaliero-Universitaria Senese, Siena, Italy., Shen X; Biostatistics Group, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.; Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, Edinburgh, UK.; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden., Ponting CP; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK., Fawkes A; Edinburgh Clinical Research Facility, Western General Hospital, University of Edinburgh, Edinburgh, UK., Tenesa A; Roslin Institute, University of Edinburgh, Edinburgh, UK.; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK.; Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, Edinburgh, UK., Caulfield M; Genomics England, London, UK.; William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK., Scott R; Genomics England, London, UK.; Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK., Rowan K; Intensive Care National Audit & Research Centre, London, UK., Murphy L; Edinburgh Clinical Research Facility, Western General Hospital, University of Edinburgh, Edinburgh, UK., Openshaw PJM; National Heart and Lung Institute, Imperial College London, London, UK.; Imperial College Healthcare NHS Trust London, London, UK., Semple MG; NIHR Health Protection Research Unit for Emerging and Zoonotic Infections, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK.; Respiratory Medicine, Alder Hey Children's Hospital, Institute in The Park, University of Liverpool, Liverpool, UK., Law A; Roslin Institute, University of Edinburgh, Edinburgh, UK., Vitart V; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK., Wilson JF; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK.; Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, Edinburgh, UK., Baillie JK; Roslin Institute, University of Edinburgh, Edinburgh, UK. j.k.baillie@ed.ac.uk.; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK. j.k.baillie@ed.ac.uk.; Intensive Care Unit, Royal Infirmary of Edinburgh, Edinburgh, UK. j.k.baillie@ed.ac.uk.
Jazyk: angličtina
Zdroj: Nature [Nature] 2021 Mar; Vol. 591 (7848), pp. 92-98. Date of Electronic Publication: 2020 Dec 11.
DOI: 10.1038/s41586-020-03065-y
Abstrakt: 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 × 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.
Databáze: MEDLINE