Since the outbreak of the COVID-19 pandemic a few months ago, doctors and researchers have been wondering about the causes behind the disparate effects of the infection, whose spectrum ranges from the absolute absence of symptoms to extremely serious symptoms such as , for example, acute respiratory distress syndrome, which cause death on more than a few occasions. What explains such variability? Does the answer reside in our genes?

TLR receivers

Coronaviruses have raised such questions for more than 15 years. In a first study of the severe acute respiratory syndrome (SARS) outbreak in 2003, Ralph Baric and colleagues at the University of North Carolina at Chapel Hill found that inactivation of a gene caused by a mutation turned mice into highly sensitive to SARS-CoV, the disease-causing coronavirus. The gene in question, TICAM2, encodes a helper protein that is involved in the activation of a family of receptors, that of the toll-like receptors (TLR). These are involved in the mechanisms of innate immunity, which constitutes the first line of defense against pathogenic microbes.

Now the focus has shifted to SARS-CoV-2, the new coronavirus responsible for COVID-19, but TLRs have garnered interest again, this time following attempts to explain the marked prevalence of sex. male among people with a serious infection.

According to a national epidemiological study carried out in France and published on April 23, up to 73 percent of those admitted by COVID-19 in intensive care units in that country were men. Differences in habits and hormonal nature would partially explain this preponderance, but genes would have something to do with the situation as well. Unlike men, women have two X chromosomes, so they have twice as many copies of the TLR7 gene, an essential detector of viral activity that enhances the immune response capacity.

Blood groups

The genetics of blood groups also seems to provide clues to a persons risk of severe coronavirus infection. In late March, Peng George Wang of the Southern China University of Science and Technology released the results of a study by his team, not yet externally reviewed, comparing the distribution of blood groups in 2,173 COVID-19 patients treated at three hospitals in the cities of Wuhan and Shenzhen with that of other uninfected citizens in those areas. Blood group A would be associated with a higher risk of contracting the virus, in contrast to type O, which would confer more protection for reasons that are still unknown.

The SARS outbreak of the past decade offers lessons. ABO blood groups are based on two types of carbohydrates (or sugars) present on the surface of red blood cells. The first corresponds to type A and the second to type B. Each sugar molecule is synthesized by an enzyme whose gene is present in two forms (one is responsible for type A and the other is responsible for type B). A third encodes an inactive version of the enzyme: type O (from the German ohne, without). The person carrying the two active enzyme variants, A and B, has type AB blood.

Both carbohydrates, A and B, act as antigens, that is, they trigger the production of antibodies that recognize the antigens that the individual lacks, which is why precautions must be taken in blood transfusions. In the ABO system, type O blood is the richest in antibodies, since it contains both anti-A and anti-B antibodies, while type AB blood does not have any.

In 2008 Jacques Le Pendu of the University of Nantes and his collaborators investigated an in vitro model of SARS-CoV. They found that the anti-A antibody neutralizes the binding of the viruss protein S to the ACE2 receptor (angiotensin-converting enzyme), a necessary step for the infection of the cell to be consumed (as soon as to anti-B antibody, data not yet available).

ACE1 versus ACE2

Another protein very close to ACE2 involved in the control of blood pressure is the angiotensin converting enzyme type 1 (ACE1). The ACE1 gene of the latter is polymorphic, that is, there are several variants (or alleles) thereof, of which D is associated with a reduced expression of the related ACE2 gene. As a result, cells carrying the ACE1 D gene have fewer receptors that serve as a gateway for the SARS-CoV virus. The frequency of the ACE1 D variant is not the same in all countries, especially in Europe, which raises the question of whether the geographical distribution of this variant could not be interrelated with the prevalence of COVID-19. Would this reflect the epidemiology of infection on a global scale? The investigations of the team led by Marc De Buyzere, at the University of Ghent, point in that direction.

Using data from 25 countries (from Portugal to Estonia and from Turkey to Finland), Belgian researchers have calculated that 38 percent of the variability in the prevalence of the disease is explained by the frequency of the D allele of ACE1. Furthermore, a similar correlation is observed in mortality statistics. They also highlight that the D allele is rare in the population of two Asian countries that have been severely affected by SARS-CoV-2.

Another genetic component that could explain vulnerability to the new coronavirus is the genes that encode human leukocyte antigens (HLA), a set of proteins that prevent the immune system from attacking the body itself. These proteins constitute the main histocompatibility complex (MHC), which marks all the cells and tissues of their own and differentiates them from everything that is not. Reid Thompson and colleagues at the Oregon Health and Science University in Portland have discovered a link between certain HLA genes and the severity of COVID-19.

People with the HLA-B * 46: 01 variant appear to be especially vulnerable to SARS-CoV-2, as was previously demonstrated with SARS-CoV. In contrast, the HLA-B * 15: 03 variant would confer a certain degree of protection. Determining a persons HLA gene envelope, using quick and inexpensive analysis, would help better predict the severity of the infection and detect those in whom vaccination would be a priority, according to the researchers.

Major projects

To learn more about the genetic variants that influence SARS-CoV-2 infection, a multitude of projects are underway. In one of them, Andrea Ganna, from the University of Helsinki, has launched the COVID-19 Host Genetics Initiative, which aims to unite the efforts of the international community of geneticists working on this issue. For his part, Jean-Laurent Casanova, from the Parisian Necker Pediatric Hospital and Rockefeller University in New York, coordinates a similar project that seeks to discover the genetic variants that favor the most serious forms of COVID-19 in minors. 50 years.

There is no doubt that we are not equal to SARS-CoV-2, but if we discover what causes such differences, perhaps we can alleviate them.

Loc Mangin

Find here all the contents of Research and Science on the COVID-19 pandemic. You can also access articles published by Scientific American and other international editions through this web.

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