Identification of genetic variants for severe COVID-19 could point to new therapies

An international team of researchers has identified several genetic variants in critically ill COVID-19 patients that could alert high-risk individuals and help doctors prescribe existing drugs in a more targeted manner.

Critical illness in COVID-19, the researchers state, is caused partly by heritable susceptibility to life-threatening infections and immune-mediated diseases.

The scientists analyzed data from 2,244 critically ill patients from 208 intensive care units in the United Kingdom. Their findings confirmed the importance of a genetic region at chr12q24.13 previously identified. In addition, they found three more genetic variants which occurred more frequently than normal in their study group who was severely ill with COVID-19. Individuals with these genetic variants are more likely to experience severe COVID-19 infection.

The work was published in Nature on Dec. 11, in its unedited, peer-reviewed form as a service to readers, the journal stated.

Susceptibility to respiratory viruses like influenza, the researchers write, is "known to be associated with specific genetic variants."

This study performed a genome-wide association study of patients critically ill with COVID-19. The control group for their study was drawn from the United Kingdom's population genetic studies. The critically ill cases came from the data base of the Genetics of Mortality in Critical Care (GenOMICC) study.

After identifying genetic variants that were overrepresented in the critically ill group, the researchers used Mendelian randomization and a transcriptome-wide association study to look further at possible causal relationships.

Mendelian randomization showed that increased expression of IFNAR2 reduced the odds of severe COVID-19. The transcriptome-wide association study in lung tissue “revealed that high expression of the monocyte/macrophage chemotactic receptor CCR2 is associated with severe COVID-19," the researchers said.

The authors state, "Our findings reveal that critical illness in COVID-19 is related to at least two biological mechanisms: innate antiviral defenses, which are known to be important early in disease [IFNAR2 and OAS genes], and host-driven inflammatory lung injury, which is a key mechanism of late, life-threatening COVID-19 [DPP9, TYK2 and CCR2]."

The researchers say, “This represents evidence for a protective role for IFNAR2 in COVID-19. Rare loss-of function mutations in IFNAR2 are associated with severe Covid-1912 and many other viral diseases.

“This suggests that administration of interferon may reduce the probability of critical illness in COVID-19, but our evidence cannot distinguish when in illness such a treatment may be effective,” the researchers propose.

Another potential target the study identified is TYK2, which plays a role in inflammatory organ injuries. They suggest further research with specific drugs to inhibit TYK2.

The paper concludes with a call for large-scale clinical trials, based on the genetic associations the researchers found.

"We have discovered new and highly plausible genetic associations with critical illness in COVID-19," they wrote. "Some of these associations lead directly to potential therapeutic approaches to augment interferon signaling, antagonize monocyte activation and infiltration into the lungs, or specifically target harmful inflammatory pathways. While this adds substantially to the biological rationale underpinning specific therapeutic approaches, each treatment must be tested in large-scale clinical trials before entering clinical practice."