The Rockefeller University »Common mutation linked to COVID mortality

Sohail Tavazoie (left) and Benjamin Ostendorf (right).

It may be COVID’s most puzzling oddity: What manifests as minor, flu-like symptoms in some individuals, turns into serious illness, disability, or even death in others. A new document published in Nature can explain the genetic basis of this dichotomy.

The researchers showed that mice with genetic variants previously linked to Alzheimer’s disease were at increased risk of death if infected with COVID. And a retrospective analysis suggested that patients with those same genetic variants were more likely to die from COVID during the pandemic. With three percent of the world’s population possessing these genetic variants, the findings could have implications for hundreds of millions of individuals globally.

“It is clear that age, gender and certain preconditions such as diabetes increase the risk of harmful outcomes, but these factors do not fully explain the spectrum of COVID outcomes,” says Sohail Tavazoie, a Leon Hess professor at Rockefeller University. “This is the first time we see such a common genetic variant associated with COVID mortality.”

A closer look at APOE

In previous work, Tavazoie’s lab studied a gene called APOE that plays a role in cancer metastasis. After showing that the gene suppresses the spread of melanoma and regulates antitumor immune responses, he and his team have begun to examine its different forms, or alleles, more closely. Most people have a module called APOE3, but 40% of the population owns at least one copy of the APOE2 or APOE4 variant. Individuals with APOE2 or APOE4 produce proteins that differ from the APOE3 protein in one or two amino acids.

One or two amino acids make a difference. Individuals with APOE4 are at increased risk of developing Alzheimer’s and atherosclerosis, and Tavazoie and Benjamin Ostendorf, a postdoctoral fellow in his lab, have shown that APOE4 and APOE2 affect the immune response against melanoma. As the pandemic progressed, Tavazoie and Ostendorf began to question whether the APOE variants might impact COVID outcomes as well. “We had only considered non-infectious diseases,” he says. “What if the APOE variants also made people vulnerable to an infectious agent, such as SARS-CoV-2? Could they cause different immune responses against a virus?

To find out, Tavazoie and colleagues first exposed more than 300 mice designed to carry human APOE to a mouse-adapted version of SARS-CoV-2 produced by colleagues Hans-Heinrich Hoffmann and Charles M. Rice. They found that mice with APOE4 and APOE2 were more likely to die than those with the more common APOE3 allele. “The results were amazing,” says Ostendorf, lead author of the study. “A difference in one or two amino acids in the APOE gene was sufficient to cause major differences in the survival of the mice exhibiting COVID.”

Mice with APOE2 and APOE4 also had more viruses replicating in the 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 findings suggest that the APOE genotype affects COVID outcomes in two ways,” says Ostendorf, “by modulating the immune response and preventing SARS-CoV-2 from infecting cells.”

Towards clinical practice

The laboratory 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 APOE4 or APOE2 were more likely to die from COVID than those with two copies of APOE3. (About three percent of individuals have two copies of APOE2 or APOE4, representing approximately 230 million people worldwide.)

Tavazoie points out that there is no evidence that 40 percent of individuals carrying just one of these alleles are at greater risk. Additionally, she states that those with two APOE2 or APOE4 alleles today are likely to be at lower risk than the data indicate. “Vaccination changes the picture,” she explains. “The data in the UK biobank spans the duration of the pandemic and many of the people who died prematurely would likely have been protected had they been vaccinated.”

Moving forward, Tavazoie hopes to see prospective studies on the link between APOE and distinct COVID outcomes. “We took the first step,” he says. “But to be clinically useful, these findings will need to be evaluated in prospective human studies that test individuals for their APOE genotypes and take into account the availability of vaccination, something that was not available at the start of the pandemic and would improve. COVID results through APOE genotypes “.

If future studies confirm a link between APOE and COVID findings, doctors might recommend that individuals with APOE4 or APOE2 have priority for vaccinations, boosters, and antiviral therapies. Screening for APOE is fairly routine and inexpensive, and many people already know their APOE variants because commercial genetic tests like 23andMe use it to assess Alzheimer’s risk. At the same time, Tavazoie warns that screening for an Alzheimer’s-related genetic variant is not without ethical hurdles, as many people would rather not know if they are predisposed to an incurable neurodegenerative disease.

For his part, Tavazoie also intends to take a closer look at how APOE interacts with various biological systems. The link between APOE4, Alzheimer’s and COVID, for example, raises the possibility that this gene may play a role in the neurocognitive complications that arise in some COVID patients. “We want to better understand the function of APOE by studying how it models the behavior of cells in these disparate contexts of cancer, dementia and now viral infection,” she says.

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