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The Association of American Medical Colleges (AAMC) published a report in January about studies being conducted on individuals who did not get infected at all but were exposed to the virus constantly, including nurses. (File image for illustrative purposes [A nurse receives a COVID-19 vaccine at Providence St. Mary Medical Center in Apple Valley, Calif., Dec. 17, 2020.] Image Credit: NYT

Even as COVID has faded into the background for most of the public, our curiosity about the virus's idiosyncrasies hasn't waned.

Why does one member of a household suffer a hacking cough but another not even a sniffle? Why does long COVID afflict some and not others? A cluster of new studies suggests some of the answers lie in our genes.

What scientists are learning could help them develop better vaccines in the future - either for new variants of COVID-19 or entirely new forms of SARS.

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Mild cases or asymptomatic infections have been relatively unstudied. Scientists' focus on the sickest patients wasn't just because of the urgency to save lives, but because it's simply easier to study people in a controlled setting like a hospital. Collecting DNA, sequencing it and then tracking healthy people out in the community is an impossibly tall order.

Before vaccinations

A team of researchers, led by the University of California, San Francisco's Jill Hollenbach, found a clever way of getting around that problem by tapping into a group of people who had already given up their DNA: bone marrow donors.

The team invited donors to participate in an ongoing project at UCSF called the COVID-19 Citizen Science Study. Hollenbach's team recruited nearly 30,000 volunteers to download an app and, when they eventually tested positive for the virus, complete a questionnaire about their symptoms.

Although they've been collecting data from that cohort for years now, this study was limited to the time before people were vaccinated so the results could be cleanly interpreted, Hollenbach says. They were looking for differences in a group of genes called HLA (short for human leukocyte antigen) that carry the recipes for proteins that help our immune cells distinguish between our own biological detritus and unwelcome invaders.

Superpower in a gene variant

The proteins show little pieces of viruses to our T-cells, which take this as an invitation to attack. Because T-cells have a long memory, they swoop in again fast the next time a similar virus invades.

The researchers found that people who carried one copy of a version of a gene called HLA-B*15:01 were more than twice as likely to remain asymptomatic after being infected with Covid. And people who inherited two copies of the gene (one from each parent) were eight times more likely to never suffer symptoms.

Hollenbach's team found that this particular flavor of HLA is very good at recognizing garden variety coronaviruses, and the T-cells exposed to those were later very good at detecting important bits of SARS-CoV-2. In other words, people with this variant who also had, say, a common cold "have this kind of superpower" of managing their Covid infection to the point where they don't have symptoms, she explains.

"I think their findings are very exciting," says Jean-Laurent Casanova, a Rockefeller University scientist who studies the relationship between our genes and susceptibility to infectious diseases. "It suggests that T-cells are involved in the early phase of SARS-CoV-2 infection, and that a strong T-cell response can blunt infection and prevent clinical manifestations."

Safe from long COVID

Another study, yet to be peer-reviewed, offers genetic ties to the other end of the spectrum: when people suffer lingering symptoms. Researchers compared about 6,500 people with a long COVID diagnosis to nearly one million people without.

People were 1.6 times more likely to develop long COVID if they had a variant in a gene called FOXP4. That same gene is also known to be a culprit in lung cancer and severe COVID.

What if you never got it despite exposure

While these studies help explain the wide range of responses to the virus, many questions remain unanswered. For example, why were some people not just asymptomatically infected, but never infected?

Casanova is interested in, say, that "health care worker without a mask in 2020 that has repeatedly tested negative, negative, negative. They're seemingly resistant to infection and we think there's a genetic basis for that." His lab is currently analyzing some 2,000 genomes among that group to try to fish out the gene responsible.

Like all science, understanding the genetic link to susceptibility is just pulling on the first thread. So much other work needs to be done to unravel the rest. Hollenbach's findings about asymptomatic COVID, for example, should prompt more exploration into alternate approaches to vaccination.

The existing vaccines all try to prevent infection altogether, but there could be merit in focusing on vaccines designed to take advantage of that memory T-cell response that seems to work so well for people with the right genetics. "Maybe you get infected, but manage it so quickly and effectively that you don't experience illness," she says.

It is important to keep unraveling these mysteries. They teach us about better ways to address this virus, which we know is here to stay, and also contribute to the broader understanding of how genes shape the immune response.