Genetic mechanisms of critical illness in Covid-19

Pairo-Castineira, E. et al. (2021) Genetic mechanisms of critical illness in Covid-19. Nature, 591(7848), pp. 92-98. (doi: 10.1038/s41586-020-03065-y) (PMID:33307546)

Abstract

Host-mediated lung inflammation is present,1 and drives mortality,2 in critical illness caused by 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(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 × 10-8) in a gene cluster encoding antiviral restriction enzyme activators (OAS1, OAS2, OAS3), on chr19p13.2 (rs2109069, p=2.3 × 10-12) near the gene encoding tyrosine kinase 2 (TYK2), on chr19p13.3 (rs2109069, p=3.98 × 10-12) within the gene encoding dipeptidyl peptidase 9 (DPP9), and on chr21q22.1 (rs2236757, p=4.99 × 10-8) in the interferon receptor gene IFNAR2. We 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 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. Large-scale randomised clinical trials will be essential before any change to clinical practice.

• Item Type: Articles
• Keywords: Genome-wide association studies, immunogenetics, SARS-CoV-2, viral infection.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Scott, Dr Janet and Ho, Dr Antonia
• Authors: Pairo-Castineira, E., Clohisey, S., Klaric, L., Bretherick, A. D., Rawlik, K., Pasko, D., Walker, S., Parkinson, N., Head Fourman, M., Russell, C. D., Furniss, J., Richmond, A., Gountouna, E., Wrobel, N., Harrison, D., Wang, B., Wu, Y., Meynert, A., Griffiths, F., Oosthuyzen, W., Kousathanas, A., Moutsianas, L., Yang, Z., Zhai, R., Zheng, C., Grimes, G., Beale, R., Millar, J., Shih, B., Keating, S., Zechner, M., Haley, C., Porteous, D. J., Hayward, C., Yang, J., Knight, J., Summers, C., Shankar-Hari, M., Klenerman, P., Turtle, L., Ho, A., Moore, S. C., Hinds, C., Horby, P., Maslove, D., Ling, L., McAuley, D., Montgomery, H., Walsh, T., Pereira, A., Renieri, A., The GenOMICC Investigators, ., The ISARIC-4C Investigators, ., The Covid-19 Human Genetics Initiative, ., 23andMe Investigators, ., BRACOVID Investigators, ., Gen-COVID Investigators, ., Shen, X., Ponting, C. P., Fawkes, A., Tenesa, A., Caulfield, M., Scott, R., Rowan, K., Openshaw, P. J.M., Semple, M. G., Law, A., Vitart, V., Wilson, J. F., and Baillie, J. K.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity; College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Virus Research
• Journal Name: Nature
• Publisher: Nature Research
• ISSN: 0028-0836
• ISSN (Online): 1476-4687
• Published Online: 11 December 2020
• Copyright Holders: Copyright © 2020 The Authors
• First Published: First published in Nature 591(7848): 92–98
• Publisher Policy: Reproduced in accordance with the publisher copyright policy