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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; Furniss, James; Richmond, Anne; Gountouna, Elvina; Wrobel, Nicola; Harrison, David; Wang, Bo; Wu, Yang; Meynert, Alison; Griffiths, Fiona; Oosthuyzen, Wilna; Kousathanas, Athanasios; Moutsianas, Loukas; Yang, Zhijian; Zhai, Ranran; Zheng, Chenqing; Grimes, Graeme; Beale, Rupert; Millar, Jonathan; Shih, Barbara; Keating, Sean; Zechner, Marie; Haley, Chris; Porteous, David J; Hayward, Caroline; Yang, Jian; Knight, Julian; Summers, Charlotte; Shankar-Hari, Manu; Klenerman, Paul; Turtle, Lance; Ho, Antonia; Moore, Shona C; Hinds, Charles; Horby, Peter; Nichol, Alistair; Maslove, David; Ling, Lowell; McAuley, Danny; Montgomery, Hugh; Walsh, Timothy.
Afiliación
  • Pairo-Castineira E; Roslin Institute, University of Edinburgh, Edinburgh, UK.
  • Clohisey S; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK.
  • Klaric L; Roslin Institute, University of Edinburgh, Edinburgh, UK.
  • Bretherick AD; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK.
  • Rawlik K; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK.
  • Pasko D; Roslin Institute, University of Edinburgh, Edinburgh, UK.
  • Walker S; Genomics England, London, UK.
  • Parkinson N; Genomics England, London, UK.
  • Fourman MH; Roslin Institute, University of Edinburgh, Edinburgh, UK.
  • Russell CD; Roslin Institute, University of Edinburgh, Edinburgh, UK.
  • Furniss J; Roslin Institute, University of Edinburgh, Edinburgh, UK.
  • Richmond A; Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
  • Gountouna E; Roslin Institute, University of Edinburgh, Edinburgh, UK.
  • Wrobel N; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK.
  • Harrison D; Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK.
  • Wang B; Edinburgh Clinical Research Facility, Western General Hospital, University of Edinburgh, Edinburgh, UK.
  • Wu Y; Intensive Care National Audit & Research Centre, London, UK.
  • Meynert A; Roslin Institute, University of Edinburgh, Edinburgh, UK.
  • Griffiths F; Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.
  • Oosthuyzen W; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK.
  • Kousathanas A; Roslin Institute, University of Edinburgh, Edinburgh, UK.
  • Moutsianas L; Roslin Institute, University of Edinburgh, Edinburgh, UK.
  • Yang Z; Genomics England, London, UK.
  • Zhai R; Genomics England, London, UK.
  • Zheng C; Biostatistics Group, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.
  • Grimes G; Biostatistics Group, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.
  • Beale R; Biostatistics Group, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.
  • Millar J; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK.
  • Shih B; The Crick Institute, London, UK.
  • Keating S; Roslin Institute, University of Edinburgh, Edinburgh, UK.
  • Zechner M; Roslin Institute, University of Edinburgh, Edinburgh, UK.
  • Haley C; Intensive Care Unit, Royal Infirmary of Edinburgh, Edinburgh, UK.
  • Porteous DJ; Roslin Institute, University of Edinburgh, Edinburgh, UK.
  • Hayward C; Roslin Institute, University of Edinburgh, Edinburgh, UK.
  • Yang J; Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK.
  • Knight J; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK.
  • Summers C; Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK.
  • Shankar-Hari M; School of Life Sciences, Westlake University, Hangzhou, China.
  • Klenerman P; Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China.
  • Turtle L; Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
  • Ho A; Department of Medicine, University of Cambridge, Cambridge, UK.
  • Moore SC; Department of Intensive Care Medicine, Guy's and St Thomas' NHS Foundation Trust, London, UK.
  • Hinds C; School of Immunology and Microbial Sciences, King's College London, London, UK.
  • Horby P; Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
  • Nichol A; NIHR Health Protection Research Unit for Emerging and Zoonotic Infections, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK.
  • Maslove D; 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.
  • Ling L; NIHR Health Protection Research Unit for Emerging and Zoonotic Infections, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK.
  • McAuley D; William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
  • Montgomery H; Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
  • Walsh T; Clinical Research Centre at St Vincent's University Hospital, University College Dublin, Dublin, Ireland.
Nature ; 591(7848): 92-98, 2021 03.
Article en En | MEDLINE | ID: mdl-33307546
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Enfermedad Crítica / COVID-19 Tipo de estudio: Clinical_trials Límite: Female / Humans / Male País/Región como asunto: Europa Idioma: En Revista: Nature Año: 2021 Tipo del documento: Article Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Enfermedad Crítica / COVID-19 Tipo de estudio: Clinical_trials Límite: Female / Humans / Male País/Región como asunto: Europa Idioma: En Revista: Nature Año: 2021 Tipo del documento: Article Pais de publicación: Reino Unido