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.
“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,” study author Sara Clohisey, a researcher at the University of Edinburgh, pointed out. “It’s more likely to be a combination of factors,” she said, which may include genetics as well as age, obesity, gender and other characteristics. (Although men are more likely to die of coronavirus infections than women, the scientists did not detect genetic variants linked to sex in this study.)
Yet Baillie said this work provides “causal evidence,” specifically for the IFNAR2 gene, and another, called TYK2, that “the products of those genes change a person’s chance of becoming critically ill with covid.”
Karlsen said “very rare, but more deleterious genetic variants in the same genes, may provide a stronger driver towards severe disease, as seen for IFNAR2.”
Interferon has been tested as a possible covid-19 therapy in clinical trials, although one large trial found giving interferon to hospitalized patients did not reduce mortality. The study authors also noted that the anti-inflammatory drug baricitinib, used to treat rheumatoid arthritis and being tested in covid-19 patients, can inhibit the protein encoded by the TYK2 gene.
The researchers plan to continue to analyze DNA samples from coronavirus patients — not only those who were severely ill and in intensive care, but also from people who had milder symptoms.
There’s no shortage of potential donors as the outbreaks continue. “The pandemic is still raging,” Clohisey said. Since they began writing this paper, she said, the researchers have tripled their DNA samples of people who have had the coronavirus.