What Is the Genetic Influence on the Severity of COVID 19?

Roxana Tabakman

November 29, 2022

A striking characteristic of COVID‑19 is that the severity of clinical outcomes is remarkably variable. Establishing a prognosis for individuals infected with COVID‑19 remains a challenge.

Since the start of the COVID‑19 pandemic, the heterogeneity of individuals who progress toward severe disease or death, along with the fact that individuals directly exposed to the virus do not necessarily become sick, supports the hypothesis that genetic risk or protective factors are at play.

In an interview with Medscape Portuguese edition, Mayana Zatz, PhD, head professor of genetics and coordinator of the Human Genome and Stem Cell Study Center at the University of São Paulo (USP), São Paulo, Brazil, explained, "The first case that caught my eye was the case of my neighbors, a couple. He presented COVID‑19 symptoms, but his wife, who took care of him, had absolutely no symptoms. I thought that it was strange, but we received 3000 emails from people saying, 'This happened to me, too.'"

Reports in the media about seven pairs of monozygotic (MZ) twins who died from COVID‑19 within days of one another in Brazil also stood out, said the researcher.

Twin studies are important for investigating the contribution of genetics vs that of the environment in the susceptibility or resistance to infectious diseases, as well as their pathology. Zatz's team analyzed the case of a 31‑year‑old Brazilian MZ twin brother pair who presented simultaneously with severe COVID‑19 and the need for oxygen support, despite their age and good health conditions. Curiously, they were admitted and intubated on the same day, but neither of the twins knew about the other's situation; they only found out when they were extubated.

The study was carried out at the USP with the collaboration of the State University of São Paulo, São Paulo, Brazil. The authors mapped the genetic profile (by sequencing the genome responsible for coding proteins, or whole‑exome sequencing) and the immune cell profile to evaluate innate and adaptive immunity.

The MZ twin brothers shared the same two rare genetic mutations, which may be associated with their increased risk of developing severe COVID‑19. However, since these variants were not studied at the protein or functional level, their pathogenicity has yet to be determined. The twins also had [human leukocyte antigen] (HLA) alleles associated with severe COVID‑19, which are important candidates for the mechanisms of innate and adaptive immunity and susceptibility to COVID‑19 infection and manifestation.

But one particular oddity stood out to the researchers: one of the brothers required longer hospitalization, and only he reported symptoms of long COVID.

In the authors' eyes, even though the patients shared genetic mutations potentially associated with the risk of developing severe COVID‑19, the differences in clinical progression emphasize that, beyond genetic risk factors, continuous exposure to pathogens over a lifetime and other environmental factors mean that each individual's immune response is unique, even in twins.

"There is no doubt that genetics contribute to the severity of COVID‑19, and environmental factors sometimes give us the opportunity to study the disease, too. Such [is the case with] MZ twins who have genetic similarities, even with changes that take place over a lifetime," José Eduardo Krieger, MD, PhD, professor of molecular medicine at the USP Medical School (FMUSP), told Medscape. "Examining MZ twins is a strategy that may help, but, with n = 2, luck really needs to be on your side to get straight to the problem. You need to combine [these findings] with other studies to solve this conundrum," said Krieger, who did not take part in the research.

Large Cohorts

Genomic and computer resources allow for the study of large sets of data from thousands of individuals. In each of those sets of data, the signal offered by thousands of markers distributed throughout the genome can be studied. This is the possibility offered by various genomic studies of large cohorts of patients with different clinical manifestations.

"Researchers examine thousands of genetic variants throughout the genome from a large sample of individuals and have the chance, for example, to identify genetic variants that are more prevalent in patients who have presented with severe disease than in those who presented with milder disease," said Krieger. "These associations highlight a chromosome region in which one or more genes explain, at least in part, the differences observed."

Genome‑wide association studies have identified some genetic variants that indicate severity of COVID‑19, with potential impact on the virus entering the cell, the immune response, or the development of cytokine storms.

One of these studies, COVID‑19 Host Genetics Initiative (COVID‑19 HGI), is an international, open-science collaboration for sharing scientific methods and resources with research groups across the world, with the goal of robustly mapping the host genetic determinants of SARS‑CoV‑2 infection and the severity of the resulting COVID‑19 disease. At the start of 2021, the COVID‑19 HGI combined genetic data from 49,562 cases and 2 million controls from 46 studies in 19 countries. A total of 853 samples from the BRACOVID study were included in the meta‑analysis. The endeavor enabled the identification of 13 genome‑wide significant loci that are associated with SARS‑CoV‑2 infection or severe manifestations of COVID‑19.

The BRACOVID study, in which Krieger participates, aims to identify host genetic factors that determine the severity of COVID‑19. It is currently the largest project of its kind in Latin America. An article provides the analysis of the first 5233 participants in the BRACOVID study, who were recruited in São Paulo, Brazil. Of these participants, 3533 had been infected with COVID‑19 and hospitalized at either the Heart Institute or the Central Institute of the FMUSP General Hospital. The remaining 1700 made up the control group, which included healthcare professionals and members of the general population. The controls were recruited through serology assays or PCR tests for SARS‑CoV‑2.

The researchers discovered a region of chromosome 1 that could play a role in modulating immune response and that could lead to an increase in the likelihood of hospitalization across a wide range of COVID‑19 risk factors. This region of chromosome 1 was only observed in Brazilians with a strong European ancestry; however, this finding had not been mentioned in previous studies, suggesting that it could harbor a risk allele specific to the Brazilian population.

The study also confirmed most, but not all, of the regions recorded in the literature, which may be significant in identifying factors determining severity that are specific to a given population.

Including information from the BRACOVID study, other studies have enhanced the knowledge on affected organs. Combined data from 14,000 patients from nine countries evaluated a region of a single chromosome and found that carriers of a certain allele had a higher probability of experiencing various COVID‑19 complications, such as severe respiratory failure, venous thromboembolism, and liver damage. The risk was even higher for individuals aged 60 years and over.

Discordant Couples

Smaller sample sizes of underrepresented populations also provide relevant data for genomic studies. Zatz's team carried out genomic studies on smaller groups, comparing serodiscordant couples (where one was infected and symptomatic while the partner remained asymptomatic and seronegative despite sharing the same bedroom during the infection). Their research found genetic variants related to immune response that were associated with susceptibility to infection and progression to severe COVID‑19. 

The team also went on to study a group of patients older than 90 years who recovered from COVID‑19 with mild symptoms or who remained asymptomatic following a positive test for SARS‑CoV‑2. They compared these patients with a sample of elderly patients from the same city (São Paulo, Brazil), sampled before the current pandemic. The researchers identified a genetic variant related to mucin production. "In individuals with mild COVID‑19, the degradation of these mucins would be more efficient," said Zatz. It is possible for this variant to interfere not only with the production of mucus, but also in its composition, as there is an exchange of amino acids in the protein.

"We continued the study by comparing the extremes, ie, those in their 90s with mild COVID‑19 and younger patients with severe COVID‑19, including several who died," said Zatz.

More Personalized Medicine

The specialists agreed that a genetic test to predict COVID‑19 severity is still a long way away. The genetic component is too little understood to enable the evaluation of individual risk. It has been possible to identify several important areas but, as Krieger pointed out, a variant identified in a certain chromosome interval may not be just one gene. There may be various candidate genes, or there may be a regulatory sequence for a distant gene. Furthermore, there are regions with genes that make sense to have an impact on COVID‑19 severity, because they regulate an inflammatory or immunologic reaction, but evidence is still lacking.

Reaching the molecular mechanism would, in future, allow a medicine to be chosen for a given patient, as already happens with other diseases. It also could enable the discovery of new medicines following as-yet-unexplored lines of research. Zatz also considers the possibility of genetic therapy.

Even with the knowledge of human genetics, one part of the equation is missing: viral genetics. "Many of the individuals who were resistant to the Delta variant were later affected by Omicron," she pointed out.

Significance of Brazil

"We have an infinite amount of genomic data worldwide, but the vast majority originates from White Americans of European origin," said Krieger. Moreover, genomic associations of COVID‑19 severity discovered in the Chinese population were not significant in the European population. Besides underscoring the importance of collaborating with international studies, this situation supports scientists' interest in carrying out genetic studies within Brazil, he added.

"In the genomic study of the Brazilian population, we found 2 million variants that were not present in the European populations," said Zatz.

Krieger mentioned a technical advantage that Brazil has. "Having been colonized by different ethnic groups and mixed many generations ago, Brazil has a population with a unique genetic structure; the recombinations are different. When preparing the samples, the regions break differently." This factor could help to separate, in a candidate region, the gene that is significant from those that might not be.

In general, severe COVID‑19 would be a complex phenomenon involving several genes and interactions with environmental factors. The Brazilian studies tried to find a factor that was unique to Brazil, but the significance of the differences remained unclear. "We found some signs that were specific to our population," concluded Krieger. "But the reason that more people in Brazil died as a result of COVID‑19 was not genetic," he added.

Mayana Zatz, PhD, and José Eduardo Krieger, MD, PhD, reported no conflicts of interest.

This article was translated from the Medscape Portuguese edition.

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