| Literature DB >> 33307546 |
Erola Pairo-Castineira1,2, Sara Clohisey1, Lucija Klaric2, Andrew D Bretherick2, Konrad Rawlik1, Dorota Pasko3, Susan Walker3, Nick Parkinson1, Max Head Fourman1, Clark D Russell1,4, James Furniss1, Anne Richmond2, Elvina Gountouna5, Nicola Wrobel6, David Harrison7, Bo Wang1, Yang Wu8, Alison Meynert2, Fiona Griffiths1, Wilna Oosthuyzen1, Athanasios Kousathanas3, Loukas Moutsianas3, Zhijian Yang9, Ranran Zhai9, Chenqing Zheng9, Graeme Grimes2, Rupert Beale10, Jonathan Millar1, Barbara Shih1, Sean Keating11, Marie Zechner1, Chris Haley1, David J Porteous5, Caroline Hayward2,5, Jian Yang12,13, Julian Knight14, Charlotte Summers15, Manu Shankar-Hari16,17, Paul Klenerman14, Lance Turtle18, Antonia Ho19, Shona C Moore18, Charles Hinds20, Peter Horby21, Alistair Nichol22,23,24, David Maslove25, Lowell Ling26, Danny McAuley27,28, Hugh Montgomery29, Timothy Walsh11, Alexandre C Pereira30,31, Alessandra Renieri32,33, Xia Shen9,34,35, Chris P Ponting2, Angie Fawkes6, Albert Tenesa1,2,34, Mark Caulfield3,20, Richard Scott3,36, Kathy Rowan7, Lee Murphy6, Peter J M Openshaw37,38, Malcolm G Semple18,39, Andrew Law1, Veronique Vitart2, James F Wilson2,34, J Kenneth Baillie40,41,42.
Abstract
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.Entities:
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Year: 2020 PMID： 33307546 DOI： 10.1038/s41586-020-03065-y
Source DB: PubMed Journal: Nature ISSN： 0028-0836 Impact factor: 69.504