Data di Pubblicazione:
2021
Abstract:
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 x 10(-8)) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 x 10(-8)) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 x 10(-12)) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 x 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.
Tipologia CRIS:
1.1 Articolo in rivista
Keywords:
2'; 5'-Oligoadenylate Synthetase; COVID-19; Chromosomes; Human; Pair 12; Chromosomes; Human; Pair 19; Chromosomes; Human; Pair 21; Critical Care; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Drug Repositioning; Female; Genome-Wide Association Study; Humans; Inflammation; Lung; Male; Multigene Family; Receptor; Interferon alpha-beta; Receptors; CCR2; TYK2 Kinase; United Kingdom; Critical Illness
Elenco autori:
Erola, Pairo-Castineira; Sara, Clohisey; Lucija, Klaric; Andrew D, Bretherick; Konrad, Rawlik; Dorota, Pasko; Susan, Walker; Nick, Parkinson; Max Head, Fourman; Clark D, Russell; James, Furniss; Anne, Richmond; Elvina, Gountouna; Nicola, Wrobel; David, Harrison; Bo, Wang; Yang, Wu; Alison, Meynert; Fiona, Griffiths; Wilna, Oosthuyzen; Athanasios, Kousathanas; Loukas, Moutsianas; Zhijian, Yang; Ranran, Zhai; Chenqing, Zheng; Graeme, Grimes; Rupert, Beale; Jonathan, Millar; Barbara, Shih; Sean, Keating; Marie, Zechner; Chris, Haley; David J, Porteous; Caroline, Hayward; Jian, Yang; Julian, Knight; Charlotte, Summers; Manu, Shankar-Hari; Paul, Klenerman; Lance, Turtle; Antonia, Ho; Shona C, Moore; Charles, Hinds; Peter, Horby; Alistair, Nichol; David, Maslove; Lowell, Ling; Danny, Mcauley; Hugh, Montgomery; Timothy, Walsh; Alexandre C, Pereira; Renieri, ; Millar, Johnny; Nichol, Alistair; Walsh, Tim; Shankar-Hari, Manu; Ponting, Chris; Meikle, Jen; Finernan, Paul; Mcmaster, Ellie; Law, Andy; Kenneth Baillie, J; Paterson, Trevor; Wackett, Tony; Armstrong, Ruth; Clark, Richard; Coutts, Audrey; Donnelly, Lorna; Gilchrist, Tammy; Hafezi, Katarzyna; Macgillivray, Louise; Maclean, Alan; Mccafferty, Sarah; Morrice, Kirstie; Weaver, Jane; Boz, Ceilia; Golightly, Ailsa; Ward, Mari; Mal, Hanning; Szoor-McElhinney, Helen; Brown, Adam; Hendry, Ross; Stenhouse, Andrew; Cullum, Louise; Law, Dawn; Law, Sarah; Law, Rachel; Swets, Maaike; Day, Nicky; Taneski, Filip; Duncan, Esther; Parkinson, Nicholas; Collier, D; Wood, S; Zak, A; Borra, C; Matharu, M; May, P; Alldis, Z; Mitchelmore, O; Bowles, R; Easthope, A; Bibi, F; Lancoma-Malcolm, I; Gurasashvili, J; Pheby, J; Shiel, J; Bolton, M; Patel, M; Taylor, M; Zongo, O; Ebano, P; Harding, P; Astin-Chamberlain, R; Choudhury, Y; Cox, A; Kallon, D; Burton, M; Hall, R; Blowes, S; Prime, Z; Biddle, J; Prysyazhna, O; Newman, T; Tierney, C; Kassam, J; Shankar-Hari, M; Ostermann, M; Campos, S; Bociek, A; Lim, R; Grau, N; O Jones, T; Whitton, C; Marotti, M; Arbane, G; Bonner, S; Hugill, K; Reid, J; Welters, I; Waugh, V; Williams, K; Shaw, D; Fernandez Roman, J; Lopez Martinez, M; Johnson, E; Waite, A; Johnston, B; Hamilton, D; Mulla, S; Mcphail, M; Smith, J; K Baillie, J; Barclay, L; Hope, D; Mcculloch, C; Mcquillan, L; Clark, S; Singleton, J; Priestley, K; Rea, N; Callaghan, M; Campbell, R; Andrew, G; Marshall, L; Mckechnie, S; Hutton, P; Bashyal, A; Davidson, N; Summers, C; Polgarova, P; Stroud, K; Pathan, N; Elston, K; Agrawal, S; Battle, C; Newey, L; Rees, T; Harford, R; Brinkworth, E; Williams, M; Murphy, C; White, I; Croft, M; Bandla, N; Gellamucho, M; Tomlinson, J; Turner, H; Davies, M; Quinn, A; Hussain, I; Thompson, C; Parker, H; Bradley, R; Griffiths, R; Scriven, J; Nilsson, A; Bates, M; Dasgin, J; Gill, J; Puxty, A; Cathcart, S; Salutous, D; Turner, L; Duffy, K; Puxty, K; Joseph, A; Herdman-Grant, R; Simms, R; Swain, A; Naranjo, A; Crowe, R; Sollesta, K; Loveridge, A; Baptista, D; Morino, E; Davey, M; Golden, D; Jones, J; Moreno Cuesta, J; Haldeos, A; Bakthavatsalam, D; Vincent, R; Elhassan, M; Xavier, K; Ganesan, A; Purohit, D; Abdelrazik, M; Morgan, J; Akeroyd, L; Bano, S; Lawton, T; Warren, D; Bromley, M; Sellick, K; Gurr, L; Wilkinson, B; Nagarajan, V; Szedlak, P; Cupitt, J; Stoddard, E; Benham, L; Preston, S; Laha, S; Slawson, N; Bradshaw, Z; Brown, J; Caswell, M; Melling, S; Bamford, P; Faulkner, M; Cawley, K; Jeffrey, H; London, E; Sainsbury, H; Nagra, I; Nasir, F; Dunmore, C; Jones, R; Abraheem, A; Al-Moasseb, M; Girach, R; Padden, G; Egan, J; Brantwood, C; Alexander, P; Bradley-Potts, J; Allen, S; Felton, T; Manna, S; Farnell-Ward, S; Leaver, S; Queiroz, J; Maccacari, E; Dawson, D; Castro Delgado, C; Pepermans Saluzzio, R; Ezeobu, O; Ding, L; Sicat, C; Kanu, R; Durrant, G; Texeira, J; Harrison, A; Samakomva, T; Scriven, J; Willis, H; Hopkins, B; Thrasyvoulou, L; Jackson, M; Zaki, A; Tibke, C; Bennett, S; Woodyatt, W; Kent, A; Goodwin, E; Brandwood, C; Clark, R; Smith, L; Rooney, K; Thomson
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