Genetic mechanisms of critical illness in COVID-19

Nature. 2021 Mar;591(7848):92-98. doi: 10.1038/s41586-020-03065-y. Epub 2020 Dec 11.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 2',5'-Oligoadenylate Synthetase / genetics
  • COVID-19 / genetics*
  • COVID-19 / pathology
  • COVID-19 / physiopathology*
  • Chromosomes, Human, Pair 12 / genetics
  • Chromosomes, Human, Pair 19 / genetics
  • Chromosomes, Human, Pair 21 / genetics
  • Critical Care
  • Critical Illness*
  • Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / genetics
  • Drug Repositioning
  • Female
  • Genome-Wide Association Study
  • Humans
  • Inflammation / genetics
  • Inflammation / pathology
  • Inflammation / physiopathology
  • Lung / pathology
  • Lung / physiopathology
  • Lung / virology
  • Male
  • Multigene Family / genetics
  • Receptor, Interferon alpha-beta / genetics
  • Receptors, CCR2 / genetics
  • TYK2 Kinase / genetics
  • United Kingdom

Substances

  • CCR2 protein, human
  • IFNAR2 protein, human
  • Receptors, CCR2
  • Receptor, Interferon alpha-beta
  • TYK2 Kinase
  • TYK2 protein, human
  • OAS1 protein, human
  • OAS2 protein, human
  • 2',5'-Oligoadenylate Synthetase
  • OAS3 protein, human
  • DPP9 protein, human
  • Dipeptidyl-Peptidases and Tripeptidyl-Peptidases