Genetic variations in testosterone receptor and COVID-19

The study proves that variants in androgen receptors are a factor influencing the worse evolution of some men with COVID-19


Description of the Study:

  • Title: Shorter androgen receptor polyQ alleles protect against life-threatening COVID-19 disease in European males.
  • Principal Investigators: Margherita Baldassarri, Nicola Picchiotti, Francesca Fava, Chiara Fallerini, Elisa Benetti, Sergio Daga, Floriana Valentino, Gabriella Doddato, Simone Furini, Annarita Giliberti, Rossella Tita, Sara Amitrano, Mirella Bruttini, Susanna Croci, Ilaria Meloni, Anna Maria Pinto, Nicola Iuso, Chiara Gabbi, Francesca Sciarra, Mary Anna Venneri, Marco Gori, Maurizio Sanarico, Francis P. Crawley, Uberto Pagotto, Flaminia Fanelli, Marco Mezzullo, Elena Dominguez-Garrido, Laura Planas-Serra, Agatha Schlüter, Roger Colobran, Pere Soler-Palacin, Pablo Lapunzina, Jair Tenorio, Aurora Pujol, Maria Grazia Castagna, Marco Marcelli, Andrea M. Isidori, Alessandra Renieri, Elisa Frullanti and Francesca Mari.
  • Centers of Implementation: University of Siena, Institut d’Investigació Biomèdica de Bellvitge (IDIBELL), Hospital Universitari Vall d’Hebron and Vall d’Hebron Institut de Recerca (VHIR).
  • Study Population:
    – Cases and controls were drawn from the Italian GEN-COVID cohort of 1178 subjects infected with SARS-CoV-2 diagnosed by RT-PCR on nasopharyngeal swab.
    – A similar Spanish cohort, composed of male COVID-19 patients (117 cases and 41 controls) was used to validate the results in another representative European population highly impacted by COVID-19.
  • Study Type: Nested case-control study (NCC).
  • Methods: Poly-amino acids variability from WES data in severely affected COVID-19 patients were compared versus SARS-CoV-2 PCR-positive oligo-asymptomatic subjects.

Objectives of the Study:

Principal Objective: To test the role of common poly-amino acid repeat polymorphisms in determining COVID-19 clinical severity.


More about this Study:

Background: While SARS-CoV-2 similarly infects men and women, COVID-19 outcome is less favorable in men. Variability in COVID-19 severity may be explained by differences in the host genome.

Added value: In a cohort of 1178 men and women with COVID-19, a supervised Machine Learning approach was used on a synthetic representation of genetic variability due to poly-amino acid repeats. Comparing the genotype of patients with extreme manifestations (severe vs. asymptomatic), an association between the poly-glutamine repeat number of the androgen receptor (AR) gene, serum testosterone concentrations, and COVID-19 outcome in male patients was found. Failure of the endocrine feedback to overcome AR signaling defects by increasing testosterone levels during the infection leads to the fact that polyQ ≥ 23 becomes dominant to testosterone levels for the clinical outcome.

GEN-COVID study: This observational study was approved by the University Hospital of Siena Ethics Review Board (Protocol n. 16917, dated March 16, 2020).

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