How Do Genes Affect How Severe
COVID-19 Will Be?

Sonya Collins

May 12, 2020

Editor's note: Find the latest COVID-19 news and guidance in Medscape's  Coronavirus Resource Center.

Some of the people hit hardest by the coronavirus are older folks and people with pre-existing health conditions, like high blood pressure, diabetes, and obesity. The potentially deadly virus seems to spare the relatively young and the generally healthy. But not all of them.

What makes one healthy young person contract the coronavirus and fight for her life on a ventilator while another gets through the infection almost symptom-free? For that matter, what makes anyone go to the hospital with COVID-19 when not everyone does? And what about people who don't catch it all? Why might all the guests at a wedding, for example, pick up the bug except for one?

The answers could be written in your genes. Researchers around the world are trying to find out which ones.

"There's reason to believe — like with almost all other diseases we've tried to go after — that genetics will impact it to some degree," says Carlos Bustamante, PhD, a professor of genetics at Stanford University and a member of the COVID-19 Host Genetics Initiative, an international consortium of genetics researchers. "The question, of course, is how do you translate that into treatment or improving outcomes in infected patients?"

The Suspects

As researchers begin to comb the human genome — that's all your estimated 25,000 genes — for genes that might play a role in COVID-19 infection, they have a few suspects in mind.

Early studies not yet published in peer-reviewed journals suggest that variations in a gene called HLA could play a role. HLA tells the body how to make specific proteins that the immune system uses to recognize intruding germs in the body. These germs are then marked as targets and killed.

computer model created by researchers at Oregon Health and Science University suggested that variations in this gene from one person to the next could result in proteins that are better or worse at recognizing and flagging the coronavirus in the body. The researchers checked this theory against previous genetic research in people who had severe acute respiratory syndrome (SARS) — caused by another type of coronavirus — during the 2002-2004 outbreak.

The theory tracked: People who had certain versions of HLA had more severe SARS infections and more of the virus in their bodies than those with other versions.

Only genetic studies in real people who have had COVID-19, rather than computer simulations, can confirm the HLA theory. Researchers are pursuing this and other theories.

The TMPRSS2 gene is another suspect. This gene, also involved in flu infection, helps create a protein that the coronavirus uses to get inside human cells. Some people produce high levels of the protein; others much less.

If research can prove that people who produce less of the protein do much better with COVID-19, "this would make very clear to us that interfering with TMPRSS2 would be an important treatment strategy," says David Goldstein, PhD, director of the Columbia University Institute for Genomic Medicine.

Researchers have their eyes on ACE2 as well. This gene helps produce ACE2 receptors on the surface of human cells. The spikey coronavirus plugs its bristles into these ACE2 ports so it can latch onto the cell. "So, ACE2 does seem the logical thing to go after in genetic research," says Bustamante.

An Open Search

But researchers say it's also important to search the human genome without assuming anything. Genetic studies can often have surprise results. Questioning only the suspects makes it possible to miss scores of other accomplices.

When Goldstein and his colleagues looked for genes that play a part in hepatitis C infection years ago, he says, "Everyone had their favorite candidate genes they were looking at. IL28B wasn't on anyone's radar." It turned out, a mutation in that unsuspected gene raises your risk for infection and tells whether the usual treatment at the time would work.

That's why researchers are exploring the entire genome of people affected in different ways by COVID-19.

Patient outliers are of particular interest.

One type of outlier is severe cases that can't be explained. "For example, someone who is under 50 and could have run the New York City Marathon last October but is now intubated in the ICU," says Jean-Laurent Casanova, MD, a professor at Rockefeller University and investigator at Howard Hughes Medical Institute. He co-founded the COVID Human Genetic Effort, an international research collaboration, with Helen Su, MD, chief of the Human Immunological Diseases Section at the National Institute of Allergy and Infectious Diseases.

The other outliers that Casanova and Su's group studies are people who have been exposed to the coronavirus again and again but, based on blood tests, never contract it. "This suggests that they are intrinsically resistant to the infection itself," says Casanova.

Research shows us that it's possible for your genes to make you immune to an infectious disease. Genes can make people immune to HIVnorovirus (a common cause of diarrhea), and other illnesses that are passed from one person to another.

Casanova and Su have collected DNA samples from a couple hundred of these COVID-19 outliers. They'll unravel their genetic code to see if these unusual cases have any gene variants, or versions, in common.

Knowledge Into Practice

Genetic researchers temper their hopes with a lump of reality: Sometimes there is no smoking gun. "The most common outcome of a genetic study is you find nothing," Goldstein says. "But it is possible that we will find gene variants that influence susceptibility to infection or the course of the disease."

Discoveries about the genetic roots of diseases — should they arise — could lead to improvements in prevention, diagnosis, and treatment.

With information about who is most likely to get the disease, based on genes, health professionals could potentially offer tailored advice about prevention. If a gene were to blame for sending otherwise healthy people to the intensive care unit, health providers could possibly observe certain COVID-19 patients with extra vigilance or provide extra preventive care after a positive test. When researchers discover a gene that can help or hinder a disease's progress, they can try to find or develop drugs that turn up or shut down that gene's activity.

"Prevention, diagnosis, and treatment — those are the three pillars of medicine," Casanova says. "I don't think you can't hope for anything better than that."

Sources:

Carlos Bustamante, PhD, professor, Stanford University, Stanford, CA.

David Goldstein, PhD, director, Columbia University Institute for Genomic Medicine.

Jean-Laurent Casanova, MD, PhD, professor, The Rockefeller University, New York City; investigator, Howard Hughes Medical Institute, Chevy Chase, MD.

The Conversation: "Your genes could determine whether the coronavirus puts you in the hospital — and we're starting to unravel which ones matter."

GeneCards: "TMPRSS2 Gene."

Cell: "SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor."

National Center for Biotechnology Information: "Gene ID: ACE2 angiotensin I converting enzyme 2 [ Homo sapiens (human) ]."

Gastroenterology: "IL28B and the Control of Hepatitis C Virus Infection."

Viruses: "CCR5: From Natural Resistance to a New Anti-HIV Strategy," "Genetic Susceptibility to Human Norovirus Infection: An Update."

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