As the coronavirus emerged, so did a mystery: Why did some who got infected never develop symptoms?
One likely explanation is it may be a person's lucky genes.
A new study published Wednesday in the scientific journal Nature suggests people with a specific version of a gene were far more likely to experience an asymptomatic infection than those without.
The relevant set of genes is known as the human leukocyte antigen, or HLA.
"This is the first time where, in a really rigorous and robust way, anybody has shown that there is a clear, definitive genetic underpinning to asymptomatic disease [from the coronavirus] — not all asymptomatic disease, but some subset of people who stay asymptomatic," said UC San Francisco neurology professor Jill Hollenbach, a co-author of the study.
Hollenbach and other researchers recruited some 30,000 people for the study — all of whom already had genetic data on file because they had registered as potential bone marrow donors with the National Marrow Donor Program.
Scientists asked those individuals to join the COVID-19 Citizen Science study, organized by researchers at UC San Francisco, and to use a smartphone app to track their coronavirus test results and any symptoms.
Researchers had a significant sample size of coronavirus-positive patients with European ancestry to generate meaningful data; there were too few test-positive participants of other ancestries for those results to be significant.
Scientists identified about 1,400 people with European ancestry who had a confirmed positive coronavirus infection in the first year of the pandemic, and all were unvaccinated because shots weren't yet available.
Of that group, 136 were asymptomatic, or roughly 10%. Reasons symptom-free people were tested could include the nature of their job, such as being a healthcare worker undergoing routine testing, or perhaps their family member had been infected and they were considered exposed to the virus.
Significantly, the scientists found that people who had a version of the gene called HLA-B*15:01 were more than twice as likely to remain asymptomatic compared with those who didn't, Hollenbach said.
And if a person had two copies of the version of this gene — one from each parent — "they were 8½ times more likely to have remained asymptomatic," Hollenbach said.
"I've been involved in these HLA disease association studies for my whole career, and we were pretty stunned, actually. That was a really strong effect," she said.
The findings follow smaller studies that suggested genetics were potentially associated with asymptomatic coronavirus infection.
Just to make sure what they were seeing was real and not something peculiar about their particular study group, the scientists also reanalyzed data in a British cohort and conducted a genetic analysis of another set of patients studied by other UC San Francisco researchers.
"We were able to replicate that same finding," Hollenbach said. "At that point, we were feeling really confident that this was a real effect."
The new study also suggests why this particular version of this gene may have helped some avoid the ravages of the worst pandemic in modern history.
One reason why the coronavirus was so deadly was that it was novel. Since it had yet to circulate, people hadn't been exposed, and many lacked immunity to combat it.
But for people with this special version of this gene, the study suggests their immune systems were somehow more readily able to target the pandemic coronavirus, officially known as SARS-CoV-2.
And the reason behind that?
After previous skirmishes with other run-of-the-mill, non-pandemic coronaviruses — the culprits behind the common cold — people with this version of this gene somehow developed the tools to better armor themselves against the pandemic strain of the coronavirus that began spreading in late 2019. There are four strains of seasonal coronaviruses that are typically responsible for 15% to 30% of respiratory tract infections annually.
Other scientists have previously suggested certain people may have had some degree of immunity to SARS-CoV-2 because of their bodies' previous experiences with seasonal coronaviruses. But with this study, scientists took the idea to another level.
To make this determination, the study's authors took samples of T cells — an important part of the body's immune system — that had been collected years before the pandemic began and introduced them to pieces of SARS-CoV-2 in a laboratory setting. The lab data show that the T cells of people with this particular version of the HLA gene managed to recognize these pieces of SARS-CoV-2 and react in a protective manner.
"Folks with this B*15:01, for whatever reason, some of them have this preexisting immunity after exposure to seasonal cold viruses that happens to be just remarkably effective at dealing with the virus" that causes COVID-19, Hollenbach said.
Having this version of the gene "is the key element to having this very effective preexisting immunity," she added.
Hollenbach said research is underway to do a similar analysis specifically for people of non-European ancestries.
The study does not suggest B*15:01 is the only explanation for why certain people were asymptomatic. Further research could unearth additional factors, including non-genetic ones.
"But for whatever reason, the previous immunity that's mediated by B*15:01 is particularly effective and gives people this chance to become infected with SARS-CoV-2 without having any symptoms at all," Hollenbach said.
The study has more than three dozen co-authors, with contributions from scientists around the world, including in Australia and Britain. In the U.S., contributions came from other scientists at UC San Francisco, the University of North Carolina at Charlotte and University of Utah, as well as the Center for International Blood and Marrow Transplant Research and the National Marrow Donor Program.
