학술논문
Genetic mechanisms of critical illness in COVID-19
Document Type
Article
Author
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; Pereira, Alexandre C.; Renieri, Alessandra; Shen, Xia; Ponting, Chris P.; Fawkes, Angie; Tenesa, Albert; Caulfield, Mark; Scott, Richard; Rowan, Kathy; Murphy, Lee; Openshaw, Peter J. M.; Semple, Malcolm G.; Law, Andrew; Vitart, Veronique; Wilson, James F.; Baillie, J. Kenneth
Source
Nature; March 2021, Vol. 591 Issue: 7848 p92-98, 7p
Subject
Language
ISSN
00280836; 14764687
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, OAS2and 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 CCR2is 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.