Why do some people have mild – or no – symptoms when infected with COVID-19, but others spiral rapidly into severe disease and even death?
A new study published in the journal Nature may have thrown light on the question.
The researchers demonstrated that mice with gene variants previously linked to Alzheimer's disease were at greater risk of dying when infected with COVID.
Retrospective analysis suggests that patients with those same gene variants were more likely to have died of COVID throughout the pandemic.
Some 3% of the world population possesses these gene variants – so the findings may have implications for hundreds of millions of individuals globally.
Sohail Tavazoie, the Leon Hess Professor at The Rockefeller University, said: "It is clear that age, sex, and certain preconditions such as diabetes increase the risk of detrimental outcomes, but these factors don't fully explain the spectrum of COVID outcomes.”
"This is the first time that we've seen such a common genetic variant associated with COVID mortality."
In previous work, Tavazoie's lab studied a gene called APOE that plays a role in cancer metastasis.
Most people have a form called APOE3, but 40% of the population carries at least one copy of the APOE2 or APOE4 variant.
Individuals with APOE2 or APOE4 produce proteins that differ from APOE3 protein by one or two amino acids.
As the pandemic progressed, Tavazoie and Ostendorf began to wonder whether APOE variants might impact COVID outcomes, too.
"We had looked only at non-infectious diseases," he says. "But what if APOE variants also made people vulnerable to an infectious agent, like SARS-CoV-2? Could they cause different immune responses against a virus?"
To find out, Tavazoie and colleagues first exposed more than 300 mice engineered to carry human APOE to a mouse-adapted version of SARS-CoV-2.
They found that mice with APOE4 and APOE2 were more likely to die than those with the more common APOE3 allele.
"The results were striking," says Ostendorf, lead author on the study. "A difference in just one or two amino acids in the APOE gene was sufficient to cause major differences in the survival of mice exhibiting COVID."
Mice with APOE2 and APOE4 also had more virus replicating in their lungs, and more signs of inflammation and tissue damage.
At the cellular level, the researchers found that APOE3 appeared to reduce the amount of virus entering the cell, while animals with the other variants had less potent immune responses to the virus.
"Taken together, these results suggest that the APOE genotype impacts COVID outcomes in two ways," Ostendorf says, "by modulating the immune response and by preventing SARS-CoV-2 from infecting cells."
The lab then turned to retrospective human studies. In an analysis of 13,000 patients in the UK Biobank, the researchers found that individuals with two copies of either APOE4 or APOE2 were more likely to have died of COVID than those with two copies of APOE3.
Roughly 3% of individuals have two copies of APOE2 or APOE4, representing an estimated 230 million people worldwide.
Tavazoie says, "We've taken the first step. But to be clinically useful, these results will need to be assessed in prospective human trials that test individuals for their APOE genotypes and account for the availability of vaccination, something that wasn't available early in the pandemic and would improve COVID outcomes across APOE genotypes."
If future studies do confirm a link between APOE and COVID outcomes, clinicians might recommend that individuals with APOE4 or APOE2 be prioritised for vaccinations, boosters, and antiviral therapies.
Screening for APOE is fairly routine and inexpensive.
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