Is COVID-19 risk genetic?

A major source of stress during the COVID-19 pandemic is uncertainty. How likely is each of us to get COVID-19? How can any of us know who might get seriously ill with the virus, given recent news reports profiling young and otherwise healthy people who have experienced serious forms of the disease?

These are exactly the sorts of answers that the much-touted field of precision medicine seeks to answer. Postdoctoral fellow Linda Kachuri, PhD, and her advisor John Witte, PhD, have begun to use precision tools to find those answers. In a recent preprint, they conducted a genome-wide association study comparing blood samples from patients who tested positive for SARS-CoV-2, the virus that causes COVID-19, to those of uninfected controls to look for genes that might make one more susceptible to infection.

Kachuri and Witte already had a project underway to which they were able to fold in the SARS-CoV-2 study as the pandemic took hold. Using blood tests of nearly 8,000 subjects from the UK Biobank, they looked for genetic factors associated with antibody response to common viruses. Viral infections are associated with variety of complex illnesses, ranging from cancers and autoimmune diseases to psychiatric conditions. Connecting the genes that affect infection, immune response and subsequent disease may point to new treatments or vaccines.

“There have been a lot of blood-based epidemiological studies, but few genetic studies looking at antibody response,” or how strong a response the body mounts to a viral invader, Kachuri said. Overly strong immune responses cause a range of poorly understood and potentially deadly syndromes, including septic shock and the so-called “cytokine storm” seen in critical cases of COVID-19.

Kachuri and Witte’s SARS-CoV-2 genome-wide association study pulls information from the biobank as it is updated twice a month to include viral test results for any study subjects who have since been tested. The study does not address the risk of severe COVID-19 illness because the biobank links only to test results; it doesn’t have any clinical information to gauge how sick the test subjects might or might not be. 

Kachuri and Witte have found that people with a particular variant in a gene called EHF, which plays a role in airway disease and inflammation, also had a higher chance of being infected with SARS-CoV-2. They also point to a possible role for tissue-specific expression of angiotensin converting enzyme 2 (ACE2) in susceptibility COVID-19. The coronavirus uses ACE2 receptors to latch on to a host’s cells, which has fueled interest in blood pressure drugs that effect the enzyme.

Curiously, while response to the other common viruses often corresponded with genetic variants in the human leukocyte antigen (HLA) region – an area of the genome crucial for the immune system’s ability to distinguish the self from invading pathogens – that region doesn’t seem to influence susceptibility to the new coronavirus.

A Italian and Spanish genome-wide association study published in the New England Journal of Medicine drew from patients’ electronic health records to focus on the most severe cases of COVID-19. It pointed to different, but not contradictory, potential genetic risk factors. For instance, it found a link to a spot on the genome that encodes a known interaction partner with ACE2, again suggesting that the enzyme may play a significant role in COVID-19.

Among those who had COVID-19 in this group, those with type A blood were much more likely to require supplemental oxygen or a ventilator. Kachuri has not found evidence that blood type plays a role in susceptibility to the virus. “It could play a role in COVID-19 severity, but not susceptibility to SARS-CoV-2 infection, which is what my analysis has investigated,” she said.

The original arm of Kachuri and Witte’s study, linking genetic factors to immune response to common viruses, also found novel associations. The research suggests that a variant in a gene called STING1 affects antibody response to Merkel cell polyomavirus (MCV), a common virus that causes a rare, deadly form of skin cancer called Merkel cell carcinoma. STING1 is also involved in immune mechanisms that are co-opted by cancers; it is being explored as a possible cancer immunotherapy target.

By identifying the genes that make people more susceptible to common viruses and those that may lead to out-of-balance immune responses to viral infections, genetic research can bring us closer to the dream of getting an individual risk assessment for everything from common cancers to COVID-19. In the age-old arms race between viruses and their human hosts, we need all the strategic intelligence we can get.