Could Genetics Explain Why Some COVID-19 Patients Fare Worse Than Others?

Certain genetic differences might separate people who fall severely ill with COVID-19 from those who contract the infection but hardly develop a cough, a new preliminary study suggests.

The research is still in its early days, though, experts say.

immune system can react to viruses thanks, in part, to specific genes that help cells spot unfamiliar bugs when they enter the body. The genes, known as human leukocyte antigen (HLA) genes, contain instructions to build proteins that bind to bits of a pathogen; those proteins serve as warning flags to alert immune cells. The immune cells, once trained to recognize these bits, jumpstart the process of building antibodies to target and destroy the invasive germ.

Within each individual, HLA genes code for three different classes of proteins; in other words, HLAs come in a variety of flavors, and depending on which HLAs you have, your body may be better or worse equipped to fight off certain germs — including SARS-CoV-2, the virus that causes COVID-19.

In a new study, published April 17 in the Journal of Virology, researchers used computer models to predict which combination of HLAs might be best at binding SARS-CoV-2, and which might be worst.

If certain HLAs can bind well to a large proportion of the virus's proteins, "we expect there to be a more protective immune response," authors Abhinav Nellore and Dr. Reid Thompson, who lead a computational biology research group at the Oregon Health and Science University, told Live Science in an email. A better bind means that the viral proteins are more likely to be presented to immune cells and prompt the production of specific antibodies, the authors said.

"If the interaction is not stable, you will not have a proper [immune] response," said Dr. Shokrollah Elahi, an associate professor in the Department of Dentistry and adjunct associate professor in the Department of Medical Microbiology and Immunology at the University of Alberta, who was not involved in the study.

But a stable bond, alone, does not guarantee the best immune response, Elahi added. If an HLA binds a viral protein that happens to be critical for the germ to replicate and survive, the subsequent antibody activity will likely target the virus more effectively than that prompted by a less important protein, Elahi said.

"This is an issue we did not address in our analysis," the authors noted. Instead, the team focused on predicting how well different HLA types could bind to bits of SARS-CoV-2. Their analysis identified six HLA types with a high capacity to bind different SARS-CoV-2 protein sequences, and three with a low capacity to do so. Specifically, a HLA type known as HLA-B*46:01 had the lowest predicted capacity to bind to bits of SARS-CoV-2.

The same HLA type cropped up in a 2003 study published in the journal BMC Medical Genetics, which assessed patients infected with SARS-CoV, a closely related coronavirus that caused an outbreak of severe acute respiratory syndrome in the early 2000s. The study found that, in a group of patients of Asian descent, the presence of HLA-B*46:01 was associated with severe cases of the infection. In their paper, the research group noted that more clinical data would be needed to confirm the connection — and the same goes for the new study of SARS-CoV-2, Nellore and Thompson said.

"The most substantial limitation of our study is that this was conducted entirely on a computer and did not involve clinical data from COVID-19 patients," the authors said. "Unless and until the findings we present here are clinically validated, they should not be employed for any clinical purposes," they added.

"In the body, we have so many things interacting," Elahi said. HLAs represent just one piece of a large, intricate puzzle that comprises the human immune system, he said. To better understand the variety of immune responses to COVID-19, Elahi and his research group aim to assess markers of immune system activity in infected patients and also catalog the ratio of immune cell types present in their bodies. While taking age, sex and other demographic factors into account, these so-called immunological profiles could help pinpoint when and why the illness takes a turn in some patients.

The clinical data could be assessed in parallel with genetic data gathered from the same patients, Elahi added. Similarly, Nellore and Thompson said that "COVID-19 testing should be paired with HLA typing, wherever [and] whenever possible," to help determine how different HLA types relate to symptom severity, if at all. Partnerships with genetic testing companies, biobanks and organ transplant registries could also offer opportunities to study HLA types in larger populations of people, they said.

"We cannot in good conscience predict at this point who will be more or less susceptible to the virus because we have not analyzed any clinical outcomes data with respect to HLA type to know that any of our predictions are valid," the authors said. If future studies support the notion that some HLA genes protect people from the virus, while others place patients at greater risk, those in the latter group could be first in line for vaccination, they added.

"In addition to prioritizing vaccinating the elderly or those with preexisting conditions, one could prioritize vaccinating people with HLA genotypes that suggest the SARS-CoV-2 virus is more likely to give them worse symptoms."

The authors went on to analyze how well HLAs can bind SARS-CoV-2 as compared with other coronaviruses, such as those that cause the common cold and infect humans often. They identified several viral bits shared between SARS-CoV-2 and at least one of these common viruses, suggesting exposure to one germ could somewhat protect the body against the other.

"If someone was previously exposed to a more common coronavirus and had the right HLA types ... then it is theoretically possible that they could also generate an earlier immune response against the novel SARS-CoV-2," the authors said. On the other hand, exposure to a similar virus could leave the body ill-equipped to fight off the new one, if, for instance, "the body is using an old set of tools that aren't ideally suited to address the new problem," the authors said.

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