Discordant couples
Smaller sample sizes of underrepresented populations also provide relevant data for genomic studies. Dr. 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), 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 Dr. 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, i.e., those in their 90s with mild COVID-19 and younger patients with severe COVID-19, including several who died,” said Dr. 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 Dr. 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 as moderators of 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. Dr. 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 Dr. 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 Dr. Zatz.
Dr. 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 Dr. Krieger. “But the reason that more people in Brazil died as a result of COVID-19 was not genetic,” he added.
Dr. Zatz and Dr. Krieger reported no conflicts of interest. This article was translated from the Medscape Portuguese edition.
A version of this article first appeared on Medscape.com.