What genetics can — and can’t — reveal about an individual’s risk of COVID

Imagine having a genetic test that could tell you your personal risk of developing complications and dying from a particular disease, such as cancer, heart attack, or even COVID. A version of such a test exists, although imperfect.

Genome-wide association studies (GWAS) are becoming an increasingly common way to assess COVID risk. The approach has the potential to fight disease by identifying locations, or loci, on the human genome that put an individual at greater or lesser risk of severe disease. Scientists hope this could eventually open the door to new forms of treatment.

“Whole genome sequencing allows you to check every base pair in the genome,” says Athanasios Kousathanas, senior genomics data scientist at London-based firm Genomics England. “And it allows you to find the particular genes that might be involved with greater precision.”

Some experts warn, however, that GWAS alone are insufficient to accurately assess COVID risk. They say genomic analysis can be difficult to disentangle from social risk factors and could leave healthcare systems open to discrimination.

Manuel Ferreira, a researcher at genetics company Regeneron, is part of a team using GWAS to hunt loci linked to COVID risk by sifting through thousands of genomes from four aggregated databases. In their most recent study, published in March in Natural geneticsFerreira and his co-authors analyzed the numbers and found that individuals carrying a rare variant of ACE2 The gene appeared to pose a nearly 40% lower risk than the general population of developing severe COVID. It’s “what we call a ‘strong effect’,” says Ferreira.

the ACE2 encodes a specialized ACE2 protein located on the surface of a cell. Normally, protein helps regulate things like blood pressure and inflammation by allowing specific protein fragments to move in or out of the cell. But it also gives SARS-CoV-2, the virus that causes COVID, a cellular entry point for infection. When the virus comes into contact with the ACE2 protein, it interlocks with its outer spike protein like a burr hanging from a sock. From there, the virus enters its target cell.

But Ferreira discovered that people carrying a specific variant of the ACE2 gene have about 39 percent fewer receptors for the protein studding their cell surfaces. The researchers hypothesize that, as a result, fewer SARS-CoV-2 viruses are able to enter these people’s bodies, significantly reducing their risk of severe COVID. “In a way, that’s not totally surprising, since we know the virus requires [these] receptors to enter the cell,” says Ferreira.

Kenneth Baillie, a clinician scientist at the University of Edinburgh, recently collaborated with Kousathanas of Genomics England on a study that identified 16 novel loci linked to severe COVID risk. Some, according to Baillie, are potential targets for new drug therapies. “I’m sure there are others who are targets for therapy whose biology we haven’t understood. [of] still pretty good,” he says.

But other researchers warn that when it comes to predicting severe COVID, it is almost impossible to disentangle genetic risks from social risk factors such as access to health care and working conditions, even in using genome-wide analysis.

Elsie Taveras is a pediatrician at Massachusetts General Hospital. But when the pandemic hit, she – like many others in her field – was brought to the intensive care unit floor to help deal with the influx of patients. Right away, she noticed a trend among people with severe COVID: Most were people of color from low-income communities. Many did not speak English.

“I never thought the most important thing I could bring to a healthcare team wasn’t so much my medical expertise,” Taveras says. “It was being able to be there because I could help this team with my Spanish language.”

Between language barriers and limited financial resources, many Taveras patients avoided seeking treatment until their illnesses worsened. Others lived in multi-generational homes or held front-line jobs in which isolation was virtually impossible. These social pressures put them at higher risk for severe COVID, not because of genetics but simply because of circumstance.

Geneticists do their best to account for such disparities in their analyses. “Epidemiologically, how can you better understand how genetics [versus social risk factors] is causing the severity” of the disease, says Taveras, is to “adapt to some of these variables”. By comparing individuals of similar ancestry, socioeconomic status, gender, or medical history, scientists can establish a baseline for a patient’s chances of developing severe COVID. But even with those controls in place, “it’s imperfect,” says Taveras.

Previous genetic analysis, for example, associated a high risk of COVID with type A blood and a low risk with blood type O. But later research found that the association between type O and COVID risk was negligible, while the link with type A blood was non-existent. .

Ferreira’s research relied on a database containing hundreds of thousands of genomes. This data gave the researchers a clear picture of the subjects’ ancestry and medical records, but virtually no context for their income level, housing situation, or primary language.

Ferreira and his colleagues found that people of European ancestry had about a 1 in 200 chance of carrying the virus reducing COVID risks ACE2 variant. In people of African descent, the odds were about one in 100, while people of South Asian descent had about a one in 25 chance (although this latter sample is very small and the result is not statistically significant). But even these estimates can be heavy.

“We have this long and complicated history about biological race as a contested category,” says Azita Chellappoo, a philosopher of medicine at the Open University, based in England. “It’s not surprising that this is something that geneticists have taken up in the context of COVID-19,” she says, even though ancestral categories often paint incomplete pictures of diversity within a population. For example, Ferreira’s study looked at the genomes of nearly 45,000 people of European descent, but only about 2,500 people of African descent and 760 of South Asian descent.

Moreover, according to Chellappoo, focusing on individual loci misses how genes interact with their environment and with each other in context. “My genes don’t do anything on their own,” she says.

But other researchers still see enormous value in finding specific COVID-related loci. “We kind of kicked the tires in the analysis,” says Baillie from Edinburgh, “and we’re still getting the same results. We are therefore very confident that these [effects] are real.”

GWAS have also been used to identify loci associated with loss of taste and smell in COVID patients, as well as markers associated with the development of pneumonia after COVID infection. Future GWAS investigations could shed light on the mysteries of lingering symptoms known collectively as long COVID.

Ultimately, Chellappoo, Baillie and others agree that genomic analysis holds potential for developing the next generation of COVID treatments. Ferreira’s research on the ACE2 protein, for example, could open a new avenue for preventing SARS-CoV-2 infection: blocking the receptors rather than attacking the virus itself. Current ACE2 blocking drugs, which are commonly prescribed for blood pressure control, have so far been ineffective against COVID. But Ferreira thinks a blocker specifically developed with COVID in mind might be more viable. “Our genetics suggest that blocking [ACE2] would be helpful,” says Ferreira. And with vaccines, antiviral drugs and monoclonal antibodies still in short supply around the world, new therapies are desperately needed.

When it comes to assessing severe COVID risk, the key is to balance internal and external factors. “There is definitely value in understanding the genetic contribution,” Taveras says, as long as we keep in mind “that there is also a relative contribution to disease severity from these social risk factors that we cannot measure as precisely as a genetic factor”. mutation.”

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