Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development.
Investigators from the Genomic consortium, which is a global collaboration studying genetics in critical illness, has compared the genetic information of patients in intensive care units (ICU) diagnosed with the coronavirus disease 2019 (COVID-19) with samples provided by healthy volunteers from other current studies, such as 100,000 Genomes and Generation Scotland. The aim of this comparison was to identify genes that could help the understanding of how COVID-19 damages lungs at the molecular level.
The study, published in the journal Nature, analyzed the DNA from 2,700 of the participants who were in the ICU and found differences in 5 of their genes when compared to those of the healthy samples. The genes, IFNAR2, TYK2, OAS1, DPP9 and CCR2, can potentially begin to explain why some patients with COVID-19 become severely sick, while others are less effected by the virus.
Genes were implicated in two important molecular processes, antiviral immunity and lung inflammation, which the investigators used to predict the effect of certain therapies. For example, it was shown that a reduction in the activity of the TYK2 gene can protect against Covid-19. JAK inhibitors, a class of anti-inflammatory drugs, are able to produce this effect.
"This is a stunning realization of the promise of human genetics to help understand critical illness,” Kenneth Baillie, the study’s chief investigator said. “Just like in sepsis and influenza, in Covid-19, damage to the lungs is caused by our own immune system, rather than the virus itself."
Findings also demonstrated that boosting the activity of the gene INFAR2 may help to create protection from COVID-19, due to the fact it is likely to mimic the effect of treatment with proteins released by cells of the immune system to defend against viruses. The team, based on these results, recommend that clinical trials should focus on targeting the pathways with drugs that are known to impact them.
"Our results immediately highlight which drugs should be at the top of the list for clinical testing. We can only test a few drugs at a time, so making the right choices will save thousands of lives,” Baillie said.