Why do some people have mild (or no) symptoms when infected with COVID-19, but others rapidly progress to severe illness and even death?
A new study published in the journal Nature may have shed some light on the matter.
The researchers showed that mice with genetic variants previously linked to Alzheimer’s disease had an increased risk of dying when infected with COVID.
The retrospective analysis suggests that patients with these same genetic variants were more likely to have died from COVID during the pandemic.
About 3% of the world’s population has these genetic variants, so the findings may have implications for hundreds of millions of individuals worldwide.
Sohail Tavazoie, the Leon Hess Professor at Rockefeller University, said: “It is clear that age, sex and certain pre-existing conditions such as diabetes increase the risk of adverse outcomes, but these factors do not fully explain the spectrum of outcomes of COVID.”
“This is the first time we’ve seen such a common genetic variant associated with mortality from COVID.”
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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 the APOE3 protein by one or two amino acids.
As the pandemic progressed, Tavazoie and Ostendorf began to wonder whether APOE variants might also affect COVID outcomes.
“We had only looked at non-communicable diseases,” he says. “But what if APOE variants also made people vulnerable to an infectious agent, such as SARS-CoV-2? Could they cause different immune responses against a virus?”
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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 both APOE4 and APOE2 were more likely to die than those with the more common APOE3 allele.
“The results were surprising,” says Ostendorf, lead author of the study. “A difference in just one or two amino acids in the APOE gene was enough to cause significant differences in the survival of mice that had 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 powerful immune responses to the virus.
“Together, these results suggest that the APOE genotype affects the outcome of COVID in two ways,” says Ostendorf, “modulating the immune response and preventing SARS-CoV-2 from infecting cells.”
The lab then turned to retrospective human studies. In an analysis of 13,000 patients at the UK Biobank, researchers found that individuals with two copies of APOE4 or APOE2 were more likely to have died from COVID than those with two copies of APOE3.
About 3% of people have two copies of APOE2 or APOE4, representing about 230 million people worldwide.
Tavazoie says, “We have taken the first step. But to be clinically useful, these results will need to be evaluated in prospective human trials that evaluate individuals for their APOE genotypes and take into account the availability of vaccination, which is not was available. early in the pandemic and would improve COVID outcomes in APOE genotypes.”
If future studies confirm a link between APOE and COVID outcomes, doctors could recommend that people with APOE4 or APOE2 be prioritized for vaccines, boosters and antiviral therapies.
APOE screening is fairly routine and inexpensive.
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