A striking feature of the SARS-CoV-2 virus that has caused so much havoc around the world over the last year is how variable a response it elicits from those it infects, with some not even expressing symptoms and others becoming seriously ill. Could variation in our genetics be the answer to these differences?
With more than 150 million cases and 3 million deaths reported across the globe, COVID-19 remains a massive public health problem, despite the rapid rollout of vaccination campaigns in countries such as the U.S.
Around 85% of people infected with the virus experience mild-to-moderate flu like symptoms, or even no symptoms at all, and can recover at home. However, the remaining 15% of people experience more severe and potentially life threatening COVID-19 that requires them to be hospitalized.
Predicting who will fall into the more severe group has become the focus of many clinicians and researchers over the last year. Although a variety of factors such as increasing age, male gender, and presence of comorbidities such as diabetes, heart disease, or obesity have been shown to increase risk of being hospitalized due to SARS-CoV-2 infection, they do not account for all the observed variability in cases.
Variability in individual genetics, for example, whether someone carries certain immune system-related gene variants could help explain why some people who do not fit other risk profiles still become very ill. It could also explain why there is also variation in disease severity between those of the same age, gender, and with the same comorbidities.
“Identification of the genes involved in the immune response to infection to SARS-CoV-2, in particular, has several immunological and medical implications,” Aurélie Cobat, M.D., Ph.D., a researcher at the Laboratory of Human Genetics of Infectious Diseases at INSERM in Paris, told Clinical OMICs.
“It can provide a better understanding of the function of the genes in natural conditions of infections. It may allow the identification of patients at risk of severe form of the disease and should help the development of specific preventive or therapeutic strategies.”
Investigating COVID-19 host genetics
One of the factors that differentiates severe COVID-19 from milder cases is an overreaction of the immune system to the virus. The resulting cytokine storm leads to damage in different tissues around the body, blood clots, and breathing difficulties that often require ventilation. It’s therefore not surprising that many of the genetic associations found so far are linked to immune system genes.
The COVID Human Genetic Effort is an international consortium aiming to discover genetic variants predisposing or protecting people from developing COVID-19-related pneumonia, as well as other aspects of the disease.
Cobat is a member of this consortium and was a co-author on two papers published in Science in October last year that linked type 1 interferon (IFN) genes, which play an important role in regulating the immune system, with severe COVID-19. One study showed that around 3.5% of patients with severe COVID-19 had a genetic defect in one of thirteen genes involved in the type 1 interferon circuit such as Toll-like receptor 3 (TLR3)– and interferon regulatory factor 7 (IRF7).
“Patients with such defects are at very high risk of developing a severe form of the disease if they are infected,” says Cobat.
The other study she contributed to showed that at least 10% of people with severe COVID-19 had autoantibodies against type 1 interferon proteins IFN-α2 and IFN-ω, not found in individuals who were asymptomatic or had mild symptoms.
“Those autoantibodies were pre-existing and were a cause of severe disease rather than a consequence of infection,” notes Cobat. “Early detection of those autoantibodies could facilitate closer monitoring and allow the initiation of specific treatment as early as possible during, or even perhaps before infection.”
Another large, international group effort set up to investigate the genetics behind SARS-CoV-2 infection is the COVID-19 Host Genetics Initiative. Authors from this collaboration published a genome wide association study (GWAS) in the NEJM last summer, which showed a genetic link between variants on chromosome 3 and COVID-19 related respiratory failure. They also confirmed a previously reported association with genes related to the ABO blood group system, suggesting people in blood group A may have a higher risk of infection than those in blood group O.
There has been some debate about the validity of the blood group association, as some studies seemed to show a link whereas others have not. But in a recent large meta-analysis study, also based on data collected by members of the COVID-19 Host Genetics Initiative and published as a preprint on the medRxiv server, the association was confirmed.
The researchers also confirmed other associations in the newer analysis including a link between severe disease and protein-altering variants in the genes TYK2 and PPP1R15A, which are involved in antiviral immunity and stress-induced cell death.
“If we find the genes and pathways involved in COVID-19 severity, this may point us to druggable targets and eventually lead to successful pharmaceutical interventions,” said Brooke Wolford, Ph.D., the Analysis Team Lead for the Michigan Genomics Initiative, one of the members of the COVID-19 Host Genetics Initiative.
“As of now, it’s less about predicting an individual’s genetic risk and more about finding clues that elucidate the biological mechanisms behind disease.”
Alessandra Renieri, M.D., Ph.D., is a professor at the University of Siena and is leading GEN-COVID a collaboration involving nearly 40 Italian hospitals, researchers, and clinicians, which aims to investigate the genetics behind COVID-19 and evaluate how these findings can help improve patient care.
One risk factor linked to more severe COVID-19 is gender, as men seem to be more at risk than women. In a recent paper in the journal eLife, Renieri and colleagues found that loss of function TLR7 gene variants seem to increase the risk of more severe disease in some men (around 2% of severely affected men).
Renieri acknowledged that while important, this still only accounts for a small number of affected individuals. “The next step is to identify more common variants,” she said.
With this is mind, she and her co-workers are trying to develop a new kind of risk score combining common and rare genetic variants, as well as known clinical risk factors, to predict who is most likely to develop severe COVID-19. “The polygenic risk score, as you read in the papers today, is not enough to understand the whole picture… We are trying to find new strategies.”
When studying the genetics of infection with SARS-CoV-2 it is important to consider diversity, particularly as people of non-white origin seem to be disproportionately affected with more severe COVID-19. This is something that has been a problem with human genetic studies in the past as many large biobanks and GWAS studies have largely been based on data from Caucasian individuals of European descent.
Brazil has a very diverse population and has been hard hit by COVID-19. Iscia Lopes-Cendes, M.D., Ph.D., is a professor at the University of Campinas and published a paper in the journal Human Genome Variation in April assessing variability of COVID-19-related genes in the Brazilian population.
She and her team looked at exome sequencing data in almost 1,000 individuals. Six variants had previously been linked to COVID-19 in other studies, but an additional seven (thought to impact protein function) were exclusively found in the Brazilian population.
While its useful to know about these variants, they are very rare, said Lopes-Cendes. “If you want something that you’re going to use to make diagnosis and to inform people in terms of population about the risk, it has to be something that’s relatively common, because if it’s something that it’s too rare, it is going to be used for just a small percentage of patients,” she explained.
Diversity of sample collection is also something the COVID-19 Host Genetics Initiative, which Lopes-Cendes is contributing to, is encouraging. “We’re leading the charge into getting everyone to empower their own analysis to increase diversity and inclusion, because we are aware that genetics has been so focused on Caucasian European genetics, that it’s so hard to get anything else,” said Kumar Veerapen, Ph.D., a research fellow at the Broad Institute who is also working on the initiative.
One thing that seems clear from the research so far is that there is no simple answer to working out who is most likely to experience severe COVID-19. Similar to the multiple clinical factors that seem to play a role, such as gender and age, genetic risk also seems to be multifactorial.
Lopes-Cendes emphasizes that it’s important not to overplay the importance of genetic results. “Based on the data we currently have, the genetics has not yet offered an explanation in terms of risk factors that will overcome the [clinical] risk factors that we know already,” she noted.
“I think we have to be very careful about that… we know it’s a complex phenotype with multiple predisposing genes, which might be very complex in terms of applying this in practice.”
Heping Zhang, Ph.D., is a professor at Yale School of Public Health. He recently published a study in the journal Human Genomics analysing data from the UK Biobank to search for genetic variants linked to risk of dying from COVID-19.
He thinks genetic studies can have a major impact on patient health, but cautioned that many studies still require replication and validation, as well as functional analyses. “It’s too early for us to say, ‘we’ll take this genetic marker and then design a particular drug for it.’… But I think that if we are able to identify genetic variants with hard solid evidence behind it, in the long term, it will have implications in terms of treatment design or even development of vaccines for this particular disease.”
While she and her colleagues still have a way to go in developing a validated risk score to predict severe COVID-19, Renieri says genetic research can have a more immediate impact by helping to guide emergency drug treatments.
“For example, in our last paper on TLR7. These people are missing interferon, so you could use interferon to treat them. Of course, interferon is not the standard of care. To use interferon, or in general the appropriate drugs led by genetic markers, you have the possibility to use the drug off label. You can go to the local ethical committee and ask to use this specific drug, this could be done for single patients, or you can set up a clinical trial, we are exploring both possibilities right now.”
Genetics can also help explain the mixed responses seen with the use of drugs such as hydroxychloroquine for treatment of patients with severe disease. This off-label treatment was first recommended for treating COVID-19 patients, but this advice was later rescinded due to fears about adverse effects in patients given the drug. Renieri and colleagues have discovered that a polymorphism in the TLR3 gene, present in around 30% of Europeans, impacts the metabolism of hydroxychloroquine and is linked to poor outcomes in COVID-19 patients treated with this drug.
“Maybe hydroxychloroquine would be a good drug, but not for every patient,” said Renieri, “but you need to give it to the right patients based on their genetics.”
Cobat also said the research she and her colleagues have carried out can have a fast impact for patients. In those with IFN1 gene variants, “early administration of type I IFN in case of SARS-CoV2 infection may be beneficial in patients with such defects.”
Their discovery of autoantibodies in some patients with severe COVID-19 could also have an important impact on treatment of patients. For example, administration of convalescent plasma (one of the various treatments being tested for COVID-19 patients) could actually be harmful if it also contains autoantibodies. “Convalescent plasma should be tested to exclude those positive for autoantibodies against type I IFN,” said Cobat.
Predicting the future
It’s hard to predict how long the current pandemic will last. With vaccinations increasing around the world, and more vaccines soon to be approved, it’s tempting to be cautiously optimistic, but the widespread nature of SARS-CoV-2 suggests it is more likely to become endemic in the population than to disappear completely.
Either way, research into host genetics has a lot to offer in terms of predicting who will need the most medical care and also for developing suitable treatments and guiding the use of existing treatments in a more precise way. However, whether this research will have a meaningful impact on the current pandemic, or offer more long-term guidance into human response to SARS-CoV-2 and potentially other coronaviruses, is less certain.
“I think some of what we find may be useful to understand host viral response in general or coronavirus response in general, particularly when it comes to how our immune systems may over or under perform, thus leading to severe disease,” says Wolford.
Although many studies to date have focused on searching for gene variants linked to more severe disease using GWAS methodology. More recent efforts are also looking into the impact that epigenetic changes such as DNA methylation could have on severity of COVID-19.
Emerging science suggests that host genetics could also help explain why some people experience extended ‘long COVID’ symptoms and others do not—something that several groups are now looking into.
Large-scale genetic studies have not previously been known for their speed, as large amounts of data and analysis are needed to find meaningful information. One positive impact of the pandemic, has been the number of collaborative projects like the COVID Human Genetic Effort and COVID-19 Host Genetics Initiative that have sprung up as a result. These large collaborations are useful for speeding up the research, but also increasing the sample sizes and making results more statistically valid.
“They started being multi centric and involving the globe. To tackle a global public health problem, you have to go global in terms of the research, no single group will be able to answer the question. I think that was a very positive thing for the field,” says Lopes-Cendes.[/vc_column_text][/vc_column][/vc_row]
Impact of Epigenetics on COVID-19
Host genetic variants are one factor that influences how people respond to COVID-19, but according to Spanish researchers at the ICREA institute in Barcelona, epigenetic factors can also play an important role.
Manel Esteller, Ph.D., a professor based at the University of Barcelo and ICREA and Aurora Pujol, M.D., Ph.D., also an ICREA professor, and their colleagues carried out an epigenome-wide association study of 407 individuals with confirmed COVID-19. Of those included, 194 had mild disease not requiring hospitalization and 213 had severe COVID-19 and were admitted to hospital where they received respiratory support.
The researchers assessed the DNA methylation status of 850,000 CpG sites on the DNA of these patients using blood samples. Overall, 44 CpG sites were significantly associated with COVID-19 disease severity, 23 of which were located in the coding sequence of genes.
Similar to studies of genetic variants linked to COVID-19 disease severity, many of these genes had functions linked to immune regulation and the release of interferon by the body in response to viral infection such as AIM2 and HLA-C.
The research team created an epigenetic score based on their findings, which they tested in the validation group of patients. They found it was able to predict disease severity with a specificity of 88.18% and a sensitivity of 77.78%.
Notably, when the scientists evaluated how many people in a population sample had this score, they found 13.3% of the group tested had this signature and 86.7% did not — a similar ratio to the number of people who seem to develop severe disease versus those who do not.