After a year, one of the challenges that COVID-19 still present is why different individuals present different development of SARS-CoV-2 infection: while some cases are asymptomatic, others may have very severe symptoms or even have fatal consequences. For example, while the virus infects men and women equally, men enter the ICU more often and have the highest mortality. To understand these differences, it was launched a collaborative work led by the University of Siena in Italy. This project was validated in Spain. The validation was coordinated by Bellvitge Biomedical Research Institute (IDIBELL) with the participation of the Vall d’Hebron University Hospital and the Vall d’Hebron Research Institute (VHIR). The results of the study are published in the journal EBioMedicine.
To carry out the work, the Italian researchers used artificial intelligence methodologies to study which genes could be related to the prognosis of COVID-19. To do this, they analyzed blood samples from 638 people (men and women) in Italy and, they identified a gene with various genetic variants that were associated with the clinical course of the disease: the androgen receptor or testosterone receptor. The variants consisted of having a different number of repeats of specific amino acids, in other words, repeats of one of the pieces that construct the receptor. Depending on the person, the androgen receptor can have between 9 to 36 repeats of the amino acid glutamine.
“The results showed that less than 23 repeats of this amino acid (short repeats) is associated with a better prognosis for COVID-19. On the contrary, if the testosterone receptor has 23 repetitions or more (long repetitions), patients are at greater risk of being hospitalized in the ICU”, summarizes Dr. Aurora Pujol, researcher of the Neurometabolic Diseases group at IDIBELL and coordinator of the Spanish cohort. Although the influence of genes in COVID-19 has been one of the research interests since the beginning of the pandemic, this is the first time that it has been verified this type of variant, the different number of repetitions of an amino acid depending on the person.
As testosterone is the main male sex hormone, the second phase of the study was focused mainly on analyzing the severity of COVID-19 in men. In this case, the results obtained in the Italian population were validated in blood samples from 158 Spanish men, 117 with severe COVID-19 and 41 with asymptomatic COVID-19 or that did not require hospitalization. It was found, again, that the androgen receptor variants are a factor that influences the worse evolution of some men to COVID-19.
“The effect of these genetic variants is important in men because testosterone is the main male sex hormone. Furthermore, its receptor is encoded on the X chromosome, of which men have only one copy. In women, this effect associated with a more serious COVID-19 would be much lower since, in them, testosterone plays a less relevant role and they have two copies of the X chromosome”, explains Dr. Roger Colobran, a researcher at the Research Group in Diagnostic Immunology of VHIR and one of the authors of the study. Having two X chromosomes causes women to have two copies of the testosterone receptor, each with its number of repeats. Therefore, the global activity of the receptor and its effect on the severity of COVID-19 would depend on the number of repetitions of the two copies.
The data collection of the Spanish cohort was centralized by IDIBELL, with the participation of the Vall d’Hebron Hospital and the VHIR Diagnostic Immunology group, the Rioja Salud Foundation, the La Paz-UAM University Hospital in Madrid and the Rare Diseases (CIBERER). The experimental validations using RT-PCR and Sanger techniques in the Spanish cohort were carried out in the laboratory of Dr. Aurora Pujol, at IDIBELL. “It is essential, in this type of study, to confirm the data of Italian patients with independent cohorts, because population genetic factors may play an important role”, adds Dr. Pujol.
The testosterone receptor and the regulation of the immune response to SARS-CoV-2
The androgen or testosterone receptor has a region that can present different number of repeats of the amino acid glutamine depending on the person. The general population presents 9 to 36 repeats, and the number of repeats is directly associated with the receptor activity. Receptors with short repeats (between 9 to 22 glutamines) have higher activity, while in those with long repeats (between 23 to 36 glutamines) this activity is reduced. The current study showed that a higher number of repeats, and therefore lower receptor activity, is associated with a worse COVID-19 prognosis regardless of age. This fact is consistent with previous studies showing that men with hypogonadism, in which testosterone levels are very low, have a worse prognosis for COVID-19.
“In cases with long repetitions, the testosterone receptor is less active. This receptor is responsible for attenuating inflammation, therefore, men who have it less active will have a stronger inflammatory response that is related to the most serious symptoms of COVID-19”, reasons Dr. Colobran. Thus, those men who have a more active receptor would be more protected against the disease due to their better ability to regulate the inflammatory response that occurs.
Furthermore, in men with longer repeats (and therefore lower androgen receptor activity), blood testosterone levels were tested and found to be higher than usual. This could be because when the receptor is less active, testosterone production could be not well regulated, and testes would be continuously generating testosterone to compensate for the lack of activity of the receptor.
“The risk of these androgen receptor variants is lower than being elderly, but it helps us to understand how the disease works, why there are so many differences between individuals, and why the most serious forms develop”, highlights Dr. Pere Soler-Palacín, head of the Pediatric Infectious Pathology and Immunodeficiencies Unit of Vall d’Hebron and head of the Investigation Group on Infection in Immunosuppressed Pediatric Patients of the VHIR, who has also participated in the publication.
The researchers leading the study conclude that this finding raises the possibility that the administration of testosterone in men with a less active receptor could help improve the prognosis of the disease and decrease its mortality.
The Bellvitge Biomedical Research Institute (IDIBELL) is a biomedical research center created in 2004. It is participated by the Bellvitge University Hospital and the Viladecans Hospital of the Catalan Institute of Health, the Catalan Institute of Oncology, the University of Barcelona and the City Council of L’Hospitalet de Llobregat.
IDIBELL is a member of the Campus of International Excellence of the University of Barcelona HUBc and is part of the CERCA institution of the Generalitat de Catalunya. In 2009 it became one of the first five Spanish research centers accredited as a health research institute by the Carlos III Health Institute. In addition, it is part of the “HR Excellence in Research” program of the European Union and is a member of EATRIS and REGIC. Since 2018, IDIBELL has been an Accredited Center of the AECC Scientific Foundation (FCAECC).