Are COVID-19 Infections Based on Genes
What manifests as minor, flu-like symptoms in some people infected with the SARS-CoV-2 coronavirus can spiral into severe COVID-19 in others. A new paper published in the peer-review journal Nature may explain the genetic underpinnings of this dichotomy.
According to Rockefeller University researchers, mice with gene variants previously linked to Alzheimer's disease were at greater risk of dying when infected with COVID-19.
And a retrospective analysis suggested that patients with those same gene variants were more likely to have died throughout the COVID-19 pandemic.
This finding is essential since about 3% of the world population possesses these gene variants.
"It is clear that age, sex, and certain preconditions such as diabetes increase the risk of detrimental (COVID-19) outcomes, but these factors don't fully explain the spectrum of COVID outcomes," commented Sohail Tavazoie, the Leon Hess Professor at The Rockefeller University, in a press release issued on September 21, 2022.
"This is the first time 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. After demonstrating that the gene suppresses the spread of melanoma and regulates anti-tumor immune responses, he and his team began looking at its different forms, or alleles, more closely.
As the COVID-19 pandemic progressed, Tavazoie and the team 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 Benjamin N. Ostendorf, lead author of 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. At the same time, 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.
Tavazoie emphasizes that there is no evidence that 40% of individuals carrying only one of these alleles are at increased risk.
Moreover, he says those with two APOE2 or APOE4 alleles are likely at lower risk today than the data indicates.
"Vaccination changes the picture," he explains. "Data in UK Biobank spans the length of the pandemic, and many of the individuals who died early on would likely have been protected had they been vaccinated."
"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 confirm a link between APOE and COVID outcomes, clinicians might recommend that individuals with APOE4 or APOE2 be prioritized for vaccinations, boosters, and antiviral therapies.
Screening for APOE is relatively routine and inexpensive, and many individuals already know their APOE variants because commercial genetic tests use it to gauge Alzheimer's risk.
At the same time, Tavazoie cautions that screening for a gene variant linked to Alzheimer's is not without ethical hurdles, given that many people would rather not know whether they are predisposed to an incurable neurodegenerative disease.
Corresponding authors: Benjamin N. Ostendorf or Sohail F. Tavazoie. No industry conflicts of interest were disclosed.
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