“Looking at resistance allows us to basically understand how we can clear an infection,” said Samira Asgari, an assistant professor of genetics and genomic sciences at the Icahn School of Medicine at Mount Sinai who was not involved in the study.

To figure out how some people manage to fend off covid symptoms, researchers turned to human leukocyte antigen (HLA) genes, which play a critical role in our body’s ability to recognize and fight pathogens. These genetic warriors are “the most medically important region of the genome,” said Jill Hollenbach, a professor in the departments of neurology and epidemiology at the University of California at San Francisco.

For their study, published Wednesday in Nature, Hollenbach and her team enrolled 29,947 volunteer bone marrow donors, because high-quality genetic data was already available for this group. They asked volunteers to use their smartphones daily to track their own coronavirus infections and resulting symptoms, including a runny nose, a scratchy throat, fever or chills. Participants were also asked to record if they had taken a coronavirus test each week, and note monthly whether they had been hospitalized.

During the nine-month study period, 1,428 unvaccinated individuals reported a positive coronavirus test, and 136 of them had no symptoms. Among the asymptomatic participants, 20 percent carried a common HLA variant called HLA-B*15:01. People carrying two copies of this variant — one passed down from each parent — were more than eight times more likely to remain asymptomatic than those carrying other HLA variants.

The researchers also used the volunteers’ data to model whether nongenetic factors affected the volunteers’ chances of having an asymptomatic infection.

“There’s so many things that make you more likely to have a severe disease, like various comorbidities and weight and age and sex,” said Hollenbach. “In this case, none of those things seem to be important, particularly in having an asymptomatic outcome — it seems to be mostly driven by genetics.”

T cells and preexisting immunity

To better understand the role of genetics in asymptomatic cases, the researchers looked at samples from people who carry HLA-B*15:01 that were collected before the coronavirus pandemic. They found that these people harbored immune cells called T cells that reacted to proteins shared by SARS-CoV-2 and other seasonal coronaviruses. This suggests carriers exposed to seasonal cold viruses may have developed preexisting immunity to covid.

Although the results may explain why some asymptomatic infections occur, the study was limited to genetic data that already existed from prior work. Also, the study group was quite homogenous, with all participants self-identifying as White and 81 percent self-identifying as female.

“In terms of diversity, we cannot expand these results to all populations because we know, based on epidemiological reports, covid symptoms vary across populations,” said Asgari.

Despite the limitations, the work is an important step in understanding why asymptomatic infections occur, which may have implications for public health, vaccine design and therapeutic development, the researchers said.

“As we’ve all learned, preventing covid infection has proven to be more difficult than we thought it was going to be,” said Hollenbach. “If we could design a vaccine that maybe doesn’t stop you from getting infected but can handle the infection so readily that you don’t have any symptoms, I’d personally be very happy with that.”