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Genetic mechanisms of critical illness in Covid-19

四川生理科学杂志 2020年第4期42卷 455-455页

作者： Erola Pairo-Castineira 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 Genomics England London UK Centre for Inflammation Research The Queen’s Medical Research Institute University of Edinburgh Edinburgh UK Centre for Genomic and Experimental Medicine Institute of Genetics and Molecular Medicine University of Edinburgh Western General Hospital Edinburgh UK Edinburgh clinical Research Facility Western General Hospital University of Edinburgh Edinburgh UK Intensive Care National Audit & Research Centre London UK Institute for Molecular Bioscience The University of Queensland Brisbane Queensland Australia Biostatistics Group School of Life Sciences Sun Yat-sen University Guangzhou China The Crick Institute London UK Intensive Care Unit Royal Infirmary of Edinburgh Edinburgh UK School of Life Sciences Westlake University Hangzhou China Westlake Laboratory of Life Sciences and Biomedicine Hangzhou China Wellcome Centre for Human Genetics University of Oxford Oxford UK Department of Medicine University of Cambridge Cambridge UK 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 NIHR Health Protection Research Unit for Emerging and Zoonotic Infections Institute of Infection Veterinary and Ecological Sciences University of Liverpool Liverpool UK 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 William Harvey Research Institute Barts and the London School of Medicine and Dentistry Queen Mary University of London London UK Centre for Tropical Medicine and Global Health Nuffield Department of Medicine University of Oxford Oxford UK clinical Research Centre at St Vincent’s University Hospital Un

Host-mediated lung inflammation is present,1 and drives mortality,2 in critical illness caused by *** 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(GWAS)in 2244 critically ill Covid-19 patients from 208 UK intensive care units(ICUs).We identify and replicate novel genome-wide significant associations,on chr12q24.13(rs10735079,p=1.65[Formula:see text]10-8)in a gene cluster encoding antiviral restriction enzyme activators(OAS1,OAS2,OAS3),on chr19p13.2(rs2109069,p=2.3[Formula:see text]10-12)near the gene encoding tyrosine kinase 2(TYK2),on chr19p13.3(rs2109069,p=3.98[Formula:see text]10-12)within the gene encoding dipeptidyl peptidase 9(DPP9),and on chr21q22.1(rs2236757,p=4.99[Formula:see text]10-8)in the interferon receptor gene *** identify potential targets for repurposing of licensed medications:using Mendelian randomisation we found evidence in support of a causal link from low expression of IFNAR2,and high expression of TYK2,to life-threatening disease;transcriptome-wide association in lung tissue revealed that high expression of the monocyte/macrophage chemotactic receptor CCR2 is associated with severe *** results identify robust genetic signals relating to key host antiviral defence mechanisms,and mediators of inflammatory organ damage in *** mechanisms may be amenable to targeted treatment with existing ***-scale randomised clinical trials will be essential before any change to clinical practice.

关键词： lung drugs critical

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