Genetic Variants Linked to Risk of Getting Severe COVID-19

The discovery will not only help develop new drugs to aid in the treatment of the virus, but points to existing medications that could help severely ill patients recover.

"We have discovered new and highly plausible genetic associations with critical illness in COVID-19," an international team of researchers led by the University of Edinburgh in the UK explains in a new paper, ScienceAlert reported.

"Some of these associations lead directly to potential therapeutic approaches to augment interferon signalling, antagonise monocyte activation and infiltration into the lungs, or specifically target harmful inflammatory pathways."

The researchers conducted their research on 2,244 critically ill COVID-19 patients sourced from 208 intensive care units in the UK. Their DNA was subjected to a genome-wide association study (GWAS), in which genetic variants in individuals are analysed to determine if they can be associated with a specific trait.

Ancestry-matched control genomes were selected from the UK Biobank, a population-scale anonymised genetic database. For each COVID-19 patient, five controls were selected, excluding any known to have a positive COVID-19 test.

The GWAS turned up eight genetic sequences more common in the COVID-19 patients, validated using two independent population studies. Five of the sequences were replicated in a meta-analysis of COVID-19 patients from the COVID-19 Host Genetics Initiative and 23andMe Inc's broad respiratory phenotype.

Because most humans haven't had their genomes sequenced, this may not be particularly useful on an individual level. However, what the genes do could be used to develop treatments.

The researchers found that the sequences implicated relate to genes involved in inflammatory processes and the body's response to invading viruses.

"For example, the TYK2 gene is associated with the inflammatory responses that are known to cause the 'cytokine storm' that is responsible for the death of younger patients who contract (this) condition," said clinical senior lecturer David Strain of the University of Exeter and the British Medical Association, who was not involved in the research.

"The reason this is of interest is that there are treatments that can block (inhibit) the receptor to this (JAK receptor) and thus may present (a) therapeutic option going forward (particularly given that the individuals most likely to experience cytokine storm are lower down the priority list for vaccinations)."

Also of interest, he noted, was an association between severe COVID-19 and a genetic predisposition toward obesity. This could mean that lifestyle changes may not have much impact on COVID-19 outcomes.

The study has at least one significant limitation, Strain notes: the controls had not tested positive to COVID-19.

"Ideally, in order to differentiate between those with susceptibility to severe disease, all the controls would also have been exposed to coronavirus, and we would be comparing those who tested positive but had only mild disease with those who went on to be hospitalised," he said.

Overall, however, the team's findings suggest that two biological mechanisms are behind critical illness in COVID-19. In the early stages, the body's innate immune response to viral infection; and in the late stages, the body's inflammatory processes.

Since there are already drugs that can target these pathways - TYK2, for example, is targeted by the rheumatoid arthritis drug baricitinib - clinical trials to test the findings could be undertaken quickly.