More than a year after the first cases of COVID-19 were detected, researchers are still trying to understand why some people infected with the virus become critically ill, while others have little to no symptoms. Scientists have turned to look at the genes of patients with severe COVID-19 to understand if their bodies mount an immune defense differently than healthy patients do. A genome-wide association study published in Nature on December 11 finds that variants of five key genes responsible for antiviral immunity and lung inflammation are associated with severe COVID-19.
The findings offer potential therapeutic targets to create an effective COVID-19 treatment. “Our results immediately highlight which drugs should be at the top of the list for clinical testing,” Kenneth Baillie, a consultant in critical care medicine and a senior research fellow at the University of Edinburgh, tells Reuters.
Baillie and his colleagues analyzed the DNA of 2,244 patients across 208 UK intensive care units and compared it to matched controls who did not have a positive COVID-19 PCR test on file. They identified eight loci where variants were more common among the intensive care patients, of which five were in genes linked to the immune system—IFNAR2, TYK2, OAS1, DPP9, and CCR2.
An analysis looking into the relationship between the activity of certain genes and severe COVID-19 pointed to a lower expression of IFNAR2, a gene that encodes a building block of a receptor for interferons, which act as emergency flares to warn the immune system of an intruder and have been a target for researchers hoping to develop a COVID-19 treatment. However, administering interferon to hospitalized COVID-19 patients did not reduce mortality, according to a large clinical trial published earlier this month.
The researchers also homed in on a possible link between severe COVID-19 and higher expression levels of TYK2 and CCR2, which encode proteins used in cytokine signaling, which drives inflammation and can lead to lung injury. The anti-inflammatory drug baricitinib, typically used to treat rheumatoid arthritis, inhibits the protein encoded by the TYK2 gene and has shown promising results in treating COVID-19 when paired with remdesivir, a broad spectrum antiviral that has shown limited effectiveness against the virus by itself, according to a study published December 11 in The New England Journal of Medicine.
While the Nature study may offer clues for the genetic underpinnings of severe COVID-19 infection, finding an effective treatment in humans may still be years away. “There is no guarantee that when a gene is found, targeting that gene will result in therapeutic efficacy,” Tom Hemming Karlsen, a physician at the University of Oslo who did not participate in the new work, tells The Washington Post. “What genetics studies like this then do is they help us find very specific starting points” for further investigation.
The authors' investigation indicated that there is a causal role for IFNAR2 and TYK2. Sara Clohisey, a research fellow at the University of Edinburgh and a coauthor of the Nature study, notes that there are likely many other factors beyond these gene variants that contribute to COVID-19 disease severity.
“A chunk of the answer is in our genes,” but “it’s unlikely that a single element is fully responsible for the development of severe COVID-19,” she tells the Post. “It’s more likely to be a combination of factors,” which may include genetics as well as age, obesity, gender, and other characteristics.
Correction (December 15): A previous version of this article misinterpreted Sara Clohisey's comments about the causality of her findings. The Scientist regrets the error.