Large-scale genetic study of severe COVID reveals common risk factors

SARS-CoV-2 particles (orange; artificially colored) bud of a cell. Genetic factors influence a person’s risk of infection with the virus leading to critical COVID-19.Credit: Steve Gschmeissner/Scientific photo library

Scientists have identified a host of genetic variants that are linked to an increased risk of developing severe COVID-191. These variants affect processes ranging from immune system signaling to blood clotting, and understanding them could help researchers target new therapies for seriously ill people.

Along with other genetic studies, these results mean that “we have a stronger evidence base for understanding COVID than any other common critical care disease,” says co-author Kenneth Baillie, a critical care physician and geneticist at the University of Edinburgh. , UK.

Previous studies2,3 identified a number of genetic variants linked to severe COVID-19, defined by lung inflammation that leads to respiratory failure. To discover more variants, Baillie and his co-authors analyzed the genomes of almost 7,500 people who had been treated for severe COVID-19 in British intensive care units. The researchers then compared these genomes with those of more than 48,000 people in the general population; the team’s data suggests that people in this group did not develop severe disease.

Some risks are in the genes

This comparison uncovered 16 variants that had not been linked to critical COVID-19, some of which double the risk of becoming seriously ill. A few of the variants occur in less than 1% of people of European ancestry. But others are found in more than half of the European population. Together, these variants could explain why some people get seriously ill.

Baillie says the gene functions implicated by the new analysis suggest two potential pathways for developing severe COVID-19. Five of the connected variants play a role in an immune messaging system that relies on signaling molecules called interferons, which cells secrete in response to infection. This suggests that some people become seriously ill after their immune system fails to curb the reproduction of the virus.

The team also linked severe COVID-19 to genetic variants involved in blood clotting and mucus production. Variants in this category could predispose people to lung inflammation or clotting, meaning even relatively low levels of the virus in the body could still lead to dangerous disease.

Understanding these pathways and associated genes is “important” and provides “tons of potential targets” for therapies, says Brent Richards, a geneticist and endocrinologist at McGill University in Montreal, Canada.

Similar associations have already borne fruit. In 2020, Baillie and his colleagues cited a variant discovered in their previous research3 to suggest that an enzyme-inhibiting drug called baricitinib could treat severe COVID-19. The results of a large clinical trial, published this month on the preprint server medRxiv, now suggest that baricitinib reduces mortality rates4. This study has not yet been peer reviewed.

lost in translation

But translating a genetic association into a treatment isn’t always easy. For example, trials of drugs that target interferon signaling to treat people hospitalized with COVID-19 have so far been unsuccessful.5,6. And while the latest work is the largest genomic study of severe COVID-19 to date, the sample size is likely still too small to capture other rare variants, says University geneticist Andrea Ganna. from Helsinki.

All the same, Baillie is optimistic that the study will help provide more treatment pathways. “There’s a good chance that the many associations we’ve demonstrated will lead to new effective therapies,” he says.

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