Genetic variants that are linked to the development of life-threatening illness in patients with COVID-19 are reported in Nature. The study sheds light on the mechanisms that underpin the severe COVID-19 symptoms, highlights targets for drug development and suggests that some existing drugs could aid the recovery of seriously ill patients.
Kenneth Baillie and colleagues performed a genome-wide association study on 2,244 critically ill patients with COVID-19 from 208 intensive care units in the UK (more than 95% of the intensive care units in the UK). The authors compared the genetic makeup of these individuals to the genomes of a control group, and identified eight genetic sequences that were more common in the patients with COVID-19, five of which are replicated in additional cohorts (including one previously known locus). These sequences relate to genes that are involved in inflammatory processes and the body’s response to invading viruses. Computational follow-up analyses provided further evidence for the involvement of these sequences in critical illness caused by COVID-19 and highlighted additional candidate genes, such as TYK2 and CCR2, which are genes that encode pro-inflammatory proteins.
The findings suggest that critical illness caused by COVID-19 is underpinned by at least two biological mechanisms: innate antiviral defences, which are known to be important early in the disease, and host-driven inflammatory processes, which are a key feature of late, life-threatening COVID-19. With this in mind, the authors suggest that drugs that boost interferon signalling, target harmful inflammatory pathways and/or dampen the activation and infiltration of monocytes in the lungs, could help to treat seriously ill patients with COVID-19. Drugs that target some of the related pathways already exist. For example, TYK2 is a target of the rheumatoid arthritis treatment baricitinib and a monoclonal antibody that blocks CCR2 has been tested in early phase clinical trials for rheumatoid arthritis. Large-scale clinical trials are urgently needed to assess the use of these drugs in the treatment of COVID-19, the authors conclude.
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