(CNN) – About 20% of people who caught COVID-19 only knew they had it because it showed up on a routine screening test. They never had any symptoms. Others got it and couldn’t shake its aftereffects for months, going on to be diagnosed with long COVID.
There are myriad factors that may determine how people fare after they catch COVID-19, including their viral dose; where the virus first entered the body – the nose or maybe mouth or eyes; their age and underlying health; and the genetic characteristics of the variant that infected them, to name a few.
New research is exploring another dimension to the puzzle of how people experience this infection: genes.
A study published in the journal Nature on July 19 shows that people who carry a common change to genes that code for certain immune system molecules that sit on the surface of cells called human leukocyte antigens, or HLAs, were more likely to have COVID-19 without any symptoms.
Another study, which was recently posted online as a preprint ahead of peer review and publication, found that individuals with certain changes to genes near FOXP4, which codes for a protein active in the lungs and immune system, appear to be more likely to develop long COVID.
HLAs may ring a bell because they’re used to determine whether organs are compatible with patients who need transplants. These molecules stick up from the surface of certain white blood cells, as well as cells in many other tissues of the body.
“I kind of think of them as like an arm sticking up, and a hand at the end of the arm,” said study author Dr. Jill Hollenbach, a professor of neurology the University of California at San Francisco’s Weill Institute for Neurosciences.
Hollenbach said it’s the job of HLA molecules to present pieces of proteins to the immune system so they can be recognized if they’re ever encountered again.
Imagine, in a cell that’s ingested the virus that causes COVID-19, some of that virus gets broken down in the cell, and some of its protein fragments would migrate up to the surface, where HLA molecules would grab them and hold them out so T cells could see them she said.
T cells are immune cells that help the body recognize and remember proteins. They build a memory for the immune system so it can respond if it sees a pathogen again.
So the HLA molecule is sticking up like an arm “then held in the hand is this … small peptide fragment piece of a protein from the virus,” Hollenbach said.
There are three general groups of HLA: HLA-A, HLA-B and HLA-DR. Within these groups, there are hundreds of variations of these molecules. Hollenbach says each one will very specifically look for certain kinds of protein fragments and hold them in a certain way so T-cells can see them and learn to make antibodies against them.
Searching for genes linked to silent COVID-19
For the study, Hollenbach started with people who had been HLA-typed for a large registry of potential bone marrow donors called “Be The Match.” She invited more than 29,000 to enroll in a smartphone-based study where people reported positive test results and recorded their symptoms. The initial “discovery” group consisted of more than 1,400 people who were unvaccinated and reported they’d tested positive for COVID-19; 136 of them reported no symptoms associated with their infections.
The researchers then took a closer look at this group to see if there were any similarities in the genes that coded for their HLA molecules, and there were. People in this group were more likely to carry a gene that coded for a specific kind of HLA molecule called HLA-B*15:01.
People who had two copies of genes were eight times more likely to remain asymptomatic than those who didn’t carry these variants.
Next, Hollenbach wanted to know how that particular kind of HLA molecule might be preventing a person from getting symptoms.
It turns out that HLA-B*15:01 recognizes pieces of other kind of SARS viruses that are associated with common, seasonal respiratory infections. The protein fragments it recognizes are shared with the virus that causes COVID-19. So folks with these HLA molecules likely already had some preexisting immunity against SARS-CoV2 and were able to clear the virus before it caused symptoms, Hollenbach said.
About 20% of people who get COVID-19 won’t have any symptoms. This HLA variant is carried by about 20% of them, Hollenbach said. So it’s not the only explanation for why people might have silent infections, and researchers point out that carrying HLA-B*15:01 doesn’t guarantee that a person won’t have any symptoms.
“Doubtless there are other genetic and non-genetic factors that are important, but we don’t know what those are right now,” Hollenbach said. “We do know that in this case, this particular genetic factor is strongly associated with asymptomatic infection.”
Gene change may partly account for long COVID risk
Genes may also help explain why people end up on the other side of the COVID-19 spectrum, dealing with symptoms that linger and turn into long COVID.
For more than three years, an international group of scientists have been searching for genes that may be associated with severe COVID-19 infections.
Researchers compiled data from 24 studies involving nearly 6,500 people and compared them to more than 1 million others who served as controls.
The investigation into long COVID is an offshoot from that effort, led by scientists at the Karolinska Institute in Stockholm.
An analysis of 11 of those studies, which involved sequencing all the genes in a person’s body, and then comparing the genomes of large numbers of people, found that those who developed long COVID were likely to share DNA around a gene called FOXP4, a gene which seems to be involved in immune responses in cells in the tiny air sacs of the lungs. These cells also seem to help repair damage to the lung.
“This particular genetic variant is intriguing because it offers some insights into some underlying mechanisms associated with long COVID and suggests the presence of a genetic predisposition. However, it cannot be solely relied upon to identify individuals at risk,” said lead study author Dr. Hugo Zeberg, who is an evolutionary geneticist at Karolinska.
Genes, Zeberg said, are likely only one part of reason why someone develops long COVID, and there are probably a slew of genes involved.
People who carried this version of the genes around FOXP4 had about a 60% greater odds of developing long COVID compared with people who didn’t have the variant, according to the study, which was posted as a preprint ahead of peer review.
Zeberg said their group plans to collect more cases and add them to the investigation, which he hopes will point to other genes that may be involved, too.
“We hope that our results, will spur others in the scientific community to investigate these associations further,” he said.
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