Genetic mechanisms of critical illness in COVID-19

Pairo-Castineira, Erola and Clohisey, Sara and Klaric, Lucija and Bretherick, Andrew D. and Rawlik, Konrad and Pasko, Dorota and Walker, Susan and Parkinson, Nick and Fourman, Max Head and Russell, Clark D. and Furniss, James and Richmond, Anne and Gountouna, Elvina and Wrobel, Nicola and Harrison, David and Wang, Bo and Wu, Yang and Meynert, Alison and Griffiths, Fiona and Oosthuyzen, Wilna and Kousathanas, Athanasios and Moutsianas, Loukas and Yang, Zhijian and Zhai, Ranran and Zheng, Chenqing and Grimes, Graeme and Beale, Rupert and Millar, Jonathan and Shih, Barbara and Keating, Sean and Zechner, Marie and Haley, Chris and Porteous, David J and Hayward, Caroline and Yang, Jian and Knight, Julian and Summers, Charlotte and Shankar-Hari, Manu and Klenerman, Paul and Turtle, Lance and Ho, Antonia and Moore, Shona C and Hinds, Charles and Horby, Peter and Nichol, Alistair and Maslove, David and Ling, Lowell and McAuley, Danny and Montgomery, Hugh and Walsh, Timothy and Pereira, Alexandre C and Renieri, Alessandra and GenOMICC Investigators and ISARIC4C Investigators and COVID-19 Human Genetics Initiative and 23andMe Investigators and BRACOVID Investigators and Gen-COVID Investigators and Shen, Xia and Ponting, Chris P and Fawkes, Angie and Tenesa, Albert and Caulfield, Mark and Scott, Richard and Rowan, Kathy and Murphy, Lee and Openshaw, Peter J M and Semple, Malcolm G and Law, Andrew and Vitart, Veronique and Wilson, James F and Baillie, J Kenneth (2021) Genetic mechanisms of critical illness in COVID-19. Nature, 591 (7848). pp. 92-98. ISSN 0028-0836

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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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26 May 2023 08:50
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19 Sep 2023 03:01