There are a lot of things we have yet to know about the new virus, COVID-19, but through continuous research, it has become clear that there are certain factors that raise an individual’s risk to develop a severe case of the disease.

With the arrival of vaccines, what separates the asymptomatic patients from those who need to be hospitalised? The risk factors include being elderly, being male, being obese, and belonging to a certain race or ethnic minority. People who have an underlying chronic condition such as kidney disease, cardiovascular disease, and diabetes also increased the likelihood of a person dying from COVID-19.

However, what makes the disease puzzling is the extremely wide spectrum of symptoms associated with it. Some people only get a mild cough or don’t even develop any symptoms at all. On the other end of the spectrum, catching the virus may mean going into respiratory failure.

Experts think this disparity could be rooted in individual persons’ genetic predisposition to the disease. Scientists all over the world have been scanning huge genetic datasets and collected DNA samples from COVID-19 patients. Their hope is to find genetic signatures that could explain why some people develop life-threatening symptoms.

Genetics and COVID-19

During the early days of the pandemic, two brothers in the Netherlands, 29 and 32,  were taken to the hospital because of COVID-19. While both were previously healthy, they developed severe symptoms and had to be admitted to the ICU. Within days, the 32-year old needed ventilation and couldn’t breathe on his own. His younger brother also came down with an unusually high fever and eventually died from complications.

Only days later, another second pair of brothers, 21 and 23, were taken to separate hospitals. Both experienced difficulty in breathing and had to be placed on ventilators. CT scans also revealed that the virus had already ravaged the younger brother’s lungs. However, after staying in the hospital for more than a week, both brothers were discharged.

Because of this, Alexander Hoischen, PhD, a geneticist at Radboud University Medical Center in Nijmegen, became convinced that a genetic component plays an important role in determining a person’s COVID-19 risk. He theorized that the brothers could share a genetic trait that either strengthened or compromised their immune systems.

Academic researchers and biotech companies have formed the COVID Human Genetic Effort and the COVID-19 Host Genetics Initiative to gather data from thousands of patients in various countries. Consumer DNA testing services are also getting DNA from their customers to identify genetic links.

Through these studies, researchers could develop new treatments or even repurpose existing drugs to treat the disease. Apart from the treatment, these studies could also help researchers predict people’s COVID-19 risk, which could help guide vaccine distribution as people with greater risk factors could be prioritized.

The Genetics of Diseases

Once proven, identifying a genetic component that strongly impacts a person’s COVID-19 risk is not an unprecedented finding. One example is the sickle cell trait, which is most common among people from Africa or those of African descent. Carriers of this trait, which is characterized by having one sickle cell gene and one normal gene, are immune from malaria infection. People who have inherited two copies of the sickle cell gene from each parent, however, develop sickle cell disease.

Another example of a genetic trait that affects immunity is a specific mutation in the CCR5 gene, which provides protection against HIV. Only about 1% of the northern European population carries two copies of this mutation.

On the other hand, there are also single-gene mutations, also known as inborn errors of immunity, which degrade a person’s immune system. Some can undermine the body’s ability to fight all kinds of infections, while others can elevate a person’s risk to a specific pathogen such as the influenza virus.

Genetic Risk Factors of COVID-19

Early research on COVID-19 reveals that a subset of people with a severe case of the disease harbor similar single-gene mutations. Because they are likely rare in the general population, experts agree that a combination of the genetic factors and other risk factors could explain the severity of some extreme cases.

Joseph Petrosino, PhD, chair of molecular virology and microbiology at Baylor College of Medicine, agrees that there is definitely a genetic component associated with the severity of the disease. What’s left to know is the degree of this impact.

Hoischen and his team studied the two pairs of brothers in the Netherlands and identified a single genetic mutation as the root of the men’s severe symptoms. The team discovered this by taking blood samples from all four men and sequencing their DNA.

Their research revealed that all four men had gene mutations called TLR7, a gene involved in recognizing foreign pathogens. While the healthy version of the gene makes interferon, an immune protein that recognizes invading viruses and pathogens, the faulty version meant that they couldn’t produce enough of this protein.

Because the TLR7 gene is located on the X chromosome, it may explain why males have a higher COVID-19 risk. A woman has two X chromosomes, which means that even if one copy of the gene mutated, they will still likely have one healthy copy. On the other hand, if a man’s sole TLR7 gene has mutated, then there is no way to compensate for it.

The COVID Human Genetic Effort has also found evidence that a lack of interferons can be the culprit behind a severe case of the infection. They studied 659 people hospitalized with severe COVID-19 symptoms. From these people, 3.5% had mutations in a set of 3 genes linked to interferons known as type I interferons. A small subset of the people studied even lacked a gene entirely.

Qian Zhang, MD, a research associate at the St. Giles Laboratory of Human Genetics of Infectious Diseases at Rockefeller University, says that because there are relatively few people who get really severe COVID-19, it is possible that it is caused by their genetic difference from other people.

A second study conducted by the COVID Human Genetic Effort showed that 10% of nearly 1,000 people with severe COVID-19 symptoms produce antibodies called “autoantibodies.” Instead of fighting the virus, these antibodies attack the immune system and block type I interferon from doing its job. An overwhelming majority — around 95% — of those who possess these autoantibodies were men.

However, even though these autoantibodies were prevalent among severe COVID-19 patients, they are rare in the general population.

Through these studies, researchers suggest that people who don’t produce enough interferon could be treated using existing interferon drugs. Those with autoantibodies may also benefit from treatment with another type of interferon. Currently, there are clinical trials being held to test these treatments on hospitalized COVID-19 patients.

Zhang explains that interferon will likely not have a significant effect on the body if the person is already several days into a severe infection. Because of this, it is beneficial to use the treatment as early as possible.

Another genetic risk that needs to be considered appears to be blood type. According to a study published in the New England Journal of Medicine, among more than 1,500 Italian and Spanish people with COVID-19, the most common blood type was blood type A and the least common was blood type O. However, other scientists have yet to find meaningful associations between COVID-19 susceptibility and blood type.

The Significance of Establishing the Genetic Links to Severe COVID-19

Aside from being able to fully understand the disease and finding a proper treatment for it, establishing the genetic risk factors of COVID-19 is also crucial in improving how we manage hospitalized patients.

Identifying these genetic links would allow scientists to identify existing drugs that target specific genes. These drugs could be tested on human cells to determine their effectiveness against COVID-19. This allows experts to get a more accurate view of how the virus works.

These findings will also improve the management of hospitalized patients, allowing hospitals to accurately triage their patients according to their risks, which would now include sex, age, underlying conditions, and genetic risk factors. Doctors would also be able to identify which patients would likely need access to hospital resources like ventilators.

By studying the genetic links to the severity of the disease, experts will also be able to add more personalized treatment plans, which could result in better outcomes for patients.

 

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