A new clue to the reason some people come down with long COVID

Stéphanie Longet is an immunologist and a COVID researcher at the University of Saint-Etienne in France, and just like 10-20% of adults who were infected with the virus, she continues to have symptoms well after her infection has resolved – a condition known colloquially as long COVID.

"I got COVID one year ago and I developed some persistent symptoms," she says. "I cannot work too long. My legs are quickly exhausted. In the morning it feels like I had run a marathon during the night, and I didn't do anything, I just slept."

Longet and other scientists don't exactly know why some people develop long COVID while others don't, but preliminary research released in medRxiv in July suggests that genetics plays a role.

The new research, which was an international collaboration between dozens of scientists, describes how some people carry a version of a single gene, FOXP4, that is associated with developing long COVID. Longet calls the new research an "important element" in understanding why some people's COVID symptoms seemingly never resolve.

A surprising finding about long COVID

Long COVID only affects a small percentage of people who are infected with SARS-CoV-2, but the scope of the pandemic means that many millions of people are suffering. Roughly 25 million people in the U.S. and over 17 million people in Europe have long COVID symptoms, with many more in other parts of the world.

There isn't a universally agreed upon definition for what is considered long COVID – people experience a range of different symptoms including "fatigue, muscle pain, intestinal disorders and brain fog" and for different periods of time according to Longet, who was not involved in the new research. That's made the disease difficult for scientists to fully understand.

But the new research adds to the growing body of work showing that genetics can influence COVID outcomes. It was only a few weeks ago when NPR reported that genetics might make some people resistant to developing any COVID symptoms at all.

Jill Hollenbach, an immunologist at the University of California, San Francisco, was one of the scientists who led the research on asymptomatic COVID. She says she was "surprised and excited" about the new long COVID findings.

"The fact that the authors were able to detect this association [between the FOXP4 gene and long COVID], I think, is spectacular," Hollenbach says.

Hollenbach also thinks that the new research on long COVID is refreshing because "there's a lot of frustration on the public's part around progress" of understanding the disease and how to treat it. "There can be a perception out there amongst some people who are involved in advocacy for long COVID that it's being dismissed [by the scientific community] and I don't think that's true."

The gene that may be connected

The new study looked at DNA from 6,450 people who developed long COVID and compared it to the DNA of those who did not. Not everyone who reported long COVID symptoms in the study had a clinical diagnosis so the research team used a broad definition of long COVID as self-reported symptoms of COVID that affect day-to-day life three months after the initial infection.

When that data was analyzed, only one connection between a person's genes and whether they developed long COVID stood out – the FOXP4 gene.

The FOXP4 gene is what biologists call a "transcription factor," meaning that it helps regulate processes throughout the body but isn't responsible for any one thing in particular. The new research shows that the gene is active in the lungs and mentions that other studies have found an association between FOXP4 and lung cancer.

However, the research does not point to FOXP4 as a smoking gun. "If you have the variant of FOXP4, in theory, you could have a higher probability to develop long COVID," Longet says. "But it doesn't mean if you have the variant that you will have long COVID."

Hollenbach, who published similar work on asymptomatic COVID in the journal Nature, says the new work is "methodologically extremely sound" and that "the result appears to be really clear."

But Hollenbach is also quick to point out that the genetic effect of the FOXP4 gene is relatively small – though that's not entirely surprising. "It's uncommon to see extremely strong genetic effects," she says. "What we find in studies like this gives us insights into what the underlying pathophysiology is."

The new research hints at "some underlying immune dysregulation in the lung itself," Hollenbach says, suggesting an abnormal immune response to COVID might be causing the long-term harm. "We need to just continue to follow these breadcrumbs and see where they lead us."

That might partially explain why so many people with long COVID are having lung problems, but for other common long COVID symptoms, like brain fog and fatigue, the activity of FOXP4 doesn't provide much of a clue, meaning there's more work to be done in order to understand all facets of the disease.

Why your genes may not fully dictate your COVID destiny

The latest research shows that there are clear connections between a person's genetics and how they respond to COVID. So does this mean that every individual's COVID fate was set in stone from the day they were born?

Hollenbach doesn't think so. "I don't believe that we are unnecessarily subjected to some kind of pre-destiny according to our genes," she says. "There's going to be many genetic and non-genetic factors that are going to be in play here."

One thing that Hollenbach says the scientific community agrees upon, and that this new research reinforces, is that, "you're more likely to have long COVID If you've had a very severe bout of COVID."

Which is why, according to Hollenbach, "vaccination is still our greatest tool" in the fight against COVID because it can prevent or reduce the severity of a COVID infection, reducing the chance someone develops long COVID.

In the meantime, however, there doesn't seem to be any imminent relief for those who are already dealing with the effects of long COVID. Longet suggests that people, "find different ways to organize your life. It's what I've done a little bit."

Working different hours, making diet modifications and trying light breathing exercises are all little things researchers have found to help manage symptoms.

Despite the lack of immediate help, Longet still believes that scientists will soon figure out a way to help resolve her symptoms and the symptoms of others with long COVID. "I'm hopeful because now there are quite a lot of studies and a lot of researchers who are working on this," she says. "I believe in science, so I'm quite hopeful."

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