Scientists pinpoint genes common among people with severe coronavirus infections

The goal of the research is to develop better treatments for the disease

By Ben Guarino @ WashingtonPost.com, Dec. 14, 2020 at 8:10 a.m. EST

Certain gene variants are linked to severe coronavirus infections, according to a team of scientists in Europe who studied the genomes of 2,200 critically ill covid-19 patients. Their results provide robust support that genetic makeup plays a role in the potentially fatal illness experienced by some people infected by the coronavirus.

Diving into people’s DNA is an approach that could help answer one of the pandemic’s biggest mysteries: Why do some people have mild coronavirus cases, or no symptoms at all, while others rapidly fall ill and die? Evidence is clear that older age and underlying conditions are risk factors for increased covid-19 severity. But genetic predispositions to runaway inflammation or other harmful immune responses could also contribute to worse disease.

Knowing this, researchers are working to uncover genes closely linked with biological systems to accelerate drug development for covid-19.

“Our primary aim in this work is to find effective treatments,” said study author Kenneth Baillie, a University of Edinburgh clinical researcher and an investigator with the GenOMICC Consortium, which explores associations between genes and critical illness.

Baillie and his colleagues pinpointed eight spots on chromosomes — five of which strongly held up under further scrutiny — where variants were more common among people in intensive care. Some of the genes contain instructions for anti-viral components of the immune system, suggesting flaws in a person’s microscopic defenses that therapeutics might fix, at least in theory.

“Looking across thousands of people, there are little variations in how much there is of each signal; these variations arise because of genetic differences between people,” Baillie said. “At this scale, we can see the effect of these variations, so we can directly predict the effect of drugs that hit the immune system in the same place.”

Translating results from these types of investigations into successful therapies has, generally, been a struggle. The process often requires lengthy research even before drugs are ready to be tested in people.

“There is no guarantee that when a gene is found, targeting that gene will result in therapeutic efficacy,” said Tom Hemming Karlsen, a physician at the University of Oslo who did not participate in the new work. He added: “What genetics studies like this then do is they help us find very specific starting points” for further investigation.

In what’s known as a genome-wide association study, Baillie and his colleagues examined the genes of more than 2,000 covid-19 patients in intensive care units across Britain, and compared those with the genes of healthy people. The research, published recently in the journal Nature, aligns with earlier reports that also found variants in the genetic makeup of critically ill patients.

The new report is the “biggest published to date of its kind,” Karlsen said. He is a co-author of a paper, published earlier this year in the New England Journal of Medicine, which used the same scientific process to identify gene variants associated with severe covid-19.

That study found people with blood type A were at higher risk of severe infections, while having blood type O was somewhat associated with a protective effect. It also noted a location on chromosome 3 linked to respiratory failure.

The new work detected the link to chromosome 3, too, though how that cluster relates to severe covid-19 is not clear. What’s more, “several of the new findings are able to point quite directly to genes with known functions of relevance to the immune system or antiviral responses,” Karlsen said.

Among the new links to severe disease is a gene named IFNAR2. That gene allows cells to build a protein receptor for a potent immune molecule, dubbed interferon for its ability to interfere with viral replication. It is part of the body’s first responses against infection. But a weak interferon response could allow the virus to quickly proliferate. That, in turn, may result in a potentially deadly overcorrection when later immune defenses kick in.

The study reveals “genetic variants, particularly near genes that are involved in the so-called interferon immune response play an important role in causing a life-threatening covid-19 infection,” said Lude Franke, a statistical geneticist at the University of Groningen, who was not involved in the Nature report.

Experts cautioned these types of investigations rarely produce evidence for direct cause-and-effect relationships between specific genes and disease severity or susceptibility to infection [....]