An international study led by the RED Center for Biomedical Research (CIBER), a public consortium dependent on Carlos III Health Institute (ISCIII), It has identified genetic regions that can determine the risk of developing serious clinical forms in SARS-CoV-2 virus infection. This collaborative work, which has had the participation of the Liver and Digestive Diseases (CIBEREHD), as well as the Respiratory Diseases (CIBERES), of CIBER, has just been published in the prestigious scientific magazine 'New England Journal of Medicine'.
The study indicates that variants from two regions of the human genome are associated with an increased risk of developing respiratory failure in patients with SARS-COV-2 infection. Specifically, one of them is located on chromosome 3 and can affect the expression of genes that would favor the entry of the virus, as well as the generation of the "cytokine storm". The second region is located on chromosome 9, specifically in the gene that determines the blood group of the ABO system. In this sense, the data showed that having blood group A is associated with a 50% higher risk of needing respiratory support in case of coronavirus infection. Conversely, having blood group O confers a protective effect against the development of respiratory failure (35% less risk).
Scientists from different hospitals in Spain and Lombardy (epicenter of the pandemic in Italy) have participated in this international study and have been coordinated by geneticists from Norway and Germany. In Spain, the study has had the collaboration of CIBER through the CIBEREHD groups of the Donostia de San Sebastián University Hospital (Luis Bujanda and Jesús Bañales), the Ramón y Cajal University Hospital of Madrid (Agustín Albillos), the Hospital Vall D´Hebron de Barcelona (María Buti), the Hospital Clinic de Barcelona and EF-CLIF (Javier Fernández) and the Hospital Universitario Virgen del Rocío in Seville (Manuel Romero). The CIBERES group has also participated in the Ramón y Cajal University Hospital in Madrid (David Jiménez).
Researchers have tried to answer the question why some people are asymptomatic or have mild symptoms while others develop serious symptoms when infected with the SARS-COV-2 virus. As the directors of the participating groups explain, they have looked for the answer in the genes and have found "a strong association between certain genetic variants on chromosomes 3 and 9 and the severity of the disease caused by the coronavirus."
Collaboration between the hospitals of Spain and Lombardy
At the peak of the COVID-19 pandemic in Italy and Spain (March-April 2020), CIBER researchers from different hospitals in Spain (Euskadi, Catalonia, Madrid and Andalusia) and Italy, in the northern region of Lombardy ( epicenter of the pandemic in Europe) started a collaborative project, coordinated by genetic experts from Norway and Germany to determine, in the shortest possible time, if there is a gene predisposition that increases the risk of severe disease with pulmonary failure in coronavirus infection.
Thus, in just three weeks the project was approved by the ethics committees of the participating Spanish and Italian institutions and blood samples were collected from 1,610 COVID-19 patients who needed respiratory support (oxygen or mechanical ventilation). DNA was extracted from blood samples to study in the laboratory of Kiel (Germany) about nine million genetic variants. For this, geneticists and bioinformatics experts were counted, as well as the quick financial donation of Norwegian philanthropists.
According to the researchers participating in the CIBER, "in less than two months, all the necessary information was available to evaluate the results and compare them with a control group of 2,205 healthy controls." Thus, "a higher frequency of 26 genetic variants was identified in patients affected by respiratory failure compared to the uninfected control group, and 2 of them in particular located on chromosomes 3 (rs11385942) and 9 (rs657152) showed a potent association with gravity. "
The genetic variant of chromosome 3 encompasses a regulatory region of 6 genes that may have relevant functions in COVID-19 severity. Although the researchers estimate that it is still premature to know which of these genes could influence the course of infection, it is well known that the coronavirus binds to the ACE2 protein on the surface of cells to enter them. One of these 6 genes involved interacts with and stabilizes the ACE2 protein. Furthermore, another of these genes is related to the inflammatory immune response in the lungs in response to pathogens.
Greater frequency in young people of the genetic variant
Furthermore, the genetic variant identified on chromosome 3 was more frequent in younger people (mean age 59), which could explain, at least in part, the severity of certain cases in this age group.
On the other hand, the genetic variant identified on chromosome 9 affects the gene that determines the ABO blood group. In this sense, the data showed that blood group A is associated with a 50% higher risk of needing ventilatory support in case of coronavirus infection, while group O confers a protective effect with a 35% lower risk of respiratory insufficiency.
In addition, the frequency of both genetic variants on chromosomes 3 and 9 is significantly higher in patients who required mechanical ventilation compared to those in whom only oxygen was administered, an association that was independent of the age and sex of the patients. Therefore, the presence of these genetic variants predisposes to the development of severe forms of respiratory failure during SARS-COV-2 infection.
Identification of COVID-19 risk population
Previous research has indicated that factors such as age and chronic diseases such as diabetes and hypertension, as well as obesity, increase the risk of developing severe cases of COVID-19. However, this study demonstrates the possibility of identifying people more vulnerable to the development of severe disease with pulmonary insufficiency due to coronovirus according to their genetic characteristics, which makes it possible to identify risk groups that need special protection and to design personalized treatments.
This collaborative European study has been the first to identify genetic factors that increase the risk of developing respiratory failure in patients with COVID-19. However, it is not the only study that is investigating in this line, since there are different international consortia whose objective is to identify genetic risk characteristics of COVID-19. In this way, future studies will allow us to delve into these results.
Link to reference article: Genome-wide association study in severe Covid-19 with respiratory failure. New England Journal of Medicine 2020. DOI: 10.1056 / NEJMoa2020283.
