Everything we know about the link between genetics and Covid-19

Everything we know about the link between genetics and Covid-19

It seems likely that genetics play a crucial role in the course of Covid-19. Research has identified possible risk factors that could pave the way for better diagnosis and treatment

(Photo: Ousa Chea / Unsplash) Vaccinate, vaccinate, vaccinate. But not only that: to win the battle against Covid-19 we must also focus on therapies and on understanding the factors that determine the course of the disease in people who become infected. In recent months, the scientific community has observed great differences in the severity of symptoms and in the outcome of the infection, related for example to the age, sex and general health of patients. But not only that.

It seems increasingly likely that genetics also play a fundamental role in determining the course of Covid-19. A work just published in Nature, the result of the analysis conducted by the experts of the Covid-19 Host Genetics Initiative on the genome of over 100 thousand people positive for the infection, showed that there are at least a dozen genetic variants with "strong statistical associations with the probability individual to develop Covid-19 and to suffer the most severe symptoms of the disease ". An evidence whose clarity surprised the experts themselves: "There are few common genetic variants that can really make a difference," commented, for example, Guillaume Butler-Laporte, an expert on infectious diseases and genetic epidemiology at McGill University in Montreal, Canada: "And I don't think anyone expected to look at them so clearly."

Previous studies

Already several months ago, after more than a year from the beginning of the first wave, an Italian study published in iScience had pointed out how the severity of Covid-19 was linked to five genetic mutations. The authors of the work, the researchers of the Ceinge - Advanced Biotechnologies of Naples, had reviewed the data from about one and a half million people residing in various European countries, made available by the aforementioned Covid-19 Host Genetics Initiative, which involves 143 international research centers: through in-depth genetic analyzes, conducted through computational techniques developed ad hoc, scientists had identified five mutations on chromosome 21 capable of altering the function of two genes, Tmprss2 and MX1, making those who were carriers more exposed to more aggressive symptoms of the infection.

But let us return to the results of the recently published study, which is the most extensive so far conducted, not in terms of the number of patients involved, but of the depth of the analysis, since deals with the merger of 46 different works. The authors report that "the genetic associations found increase the risk, in general, by a relatively low percentage, even if some increases are comparable to those due to other established risk factors, including obesity and diabetes". In any case, the experts note that even if the increased risk was not that significant, the study of genetic variants related to the severity of Covid-19 is still important, since it helps shed light on the biological mechanisms underlying the disease. and, consequently, points the way to possible therapies.

Strategies against Covid-19

One of the variants identified has to do with a known family of antiviral genes, the so-called Oas (oligoadenylate synthase): These are genes that activate enzymes that bind to the RNA of the virus, and it appears that a variant leading to a lower level of the Oas1 enzyme in the lung increases the risk of infection, hospitalization and severe symptoms. Most coronaviruses "respond" to this protection mechanism using another family of proteins, phosphodiesterases (Pde), but Sars-CoV-2 does not seem capable of doing so. For this reason, drugs are being studied that can increase the levels of Oas1, exploiting this kind of "Achilles heel" of the virus.

Another variant is found in the vicinity of a gene that codes for a portion of a cellular receptor for interferons, molecules already known for their action in stimulating the immune response to viruses. Precisely because of this effect, a type of interferon had already been tested as a possible anti Covid-19 treatment even before the confirmation of the genetic correlation, but the trials did not give positive results. Still from a therapeutic point of view, other genetic associations are also being studied, including for example a protein encoded by a gene, TYK2, which appears to be related to severe symptoms of the disease and on which baricitinib, a drug currently used for the treatment of rheumatoid arthritis.

One of the objectives of this line of research is to understand if and how the correlations between genetic variants and disease severity can help predict the individual course of the infection. Perhaps, as is the case for other diseases, with the drafting of a risk score that takes into account both genetic associations and the possible presence of comorbidities such as type 2 diabetes, cancer, obesity and cardiovascular disease. But there is also another aspect, somewhat complementary, and it is that which concerns rare mutations.

According to some experts, including for example Jean-Laurent Casanova, geneticist at Rockefeller University who heads Covid Human Genetic Effort, another consortium investigating the link between genetics and Covid-19, the search for common variants that increase risk relatively little is less clinically important than the search for rarer variants that can lead to intensive care young and healthy patients. Casanova's team, for example, has identified a rare mutation involving a gene, Ifnar2, responsible for encoding a subunit of a receptor for an interferon, and which, along with others, could be linked to the development of severe pneumonia. But at the moment there are still a lot of conditionals.

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