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Title: Shorter androgen receptor polyQ alleles protect against life-threatening COVID-19 disease in European males
Author: Baldassarri, Margherita
Picchiotti, Nicola
Fava, Francesca
Fallerini, Chiara
Benetti, Elisa
Daga, Sergio
Valentino, Floriana
Doddato, Gabriella
Furini, Simone
Giliberti, Annarita
Tita, Rossella
Amitrano, Sara
Bruttini, Mirella
Croci, Susanna
Meloni, Ilaria
Pinto, Anna Maria
Iuso, Nicola
Gabbi, Chiara
Sciarra, Francesca
Venneri, Mary Anna
Gori, Marco
Sanarico, Maurizio
Crawley, Francis P.
Pagotto, Uberto
Fanelli, Flaminia
Mezzullo, Marco
Dominguez Garrido, Elena
Planas Serra, Laura
Schlüter, Agatha
Colobran, Roger
Soler Palacín, Pere
Lapunzina, Pablo
Tenorio, Jair
Pujol Onofre, Aurora
Castagna, Maria Grazia
Marcelli, Marco
Isidori, Andrea M.
Renieri, Alessandra
Frullanti, Elisa
Mari, Francesca
Spanish Covid HGE, GENCOVID Multicenter Study
Keywords: Andrògens
Issue Date: 1-Mar-2021
Publisher: Elsevier BV
Abstract: 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. Methods: We compared poly-amino acids variability from WES data in severely affected COVID-19 patients versus SARS-CoV-2 PCR-positive oligo-asymptomatic subjects. Findings: Shorter polyQ alleles (≤22) in the androgen receptor (AR) conferred protection against severe outcome in COVID-19 in the first tested cohort (both males and females) of 638 Italian subjects. The association between long polyQ alleles (≥23) and severe clinical outcome (p = 0.024) was also validated in an independent cohort of Spanish men <60 years of age (p = 0.014). Testosterone was higher in subjects with AR long-polyQ, possibly indicating receptor resistance (p = 0.042 Mann-Whitney U test). Inappropriately low serum testosterone level among carriers of the long-polyQ alleles (p = 0.0004 Mann-Whitney U test) predicted the need for intensive care in COVID-19 infected men. In agreement with the known anti-inflammatory action of testosterone, patients with long-polyQ and age ≥60 years had increased levels of CRP (p = 0.018, not accounting for multiple testing). Interpretation: We identify the first genetic polymorphism that appears to predispose some men to develop more severe disease. Failure of the endocrine feedback to overcome AR signaling defects by increasing testosterone levels during the infection leads to the polyQ tract becoming dominant to serum testosterone levels for the clinical outcome. These results may contribute to designing reliable clinical and public health measures and provide a rationale to test testosterone as adjuvant therapy in men with COVID-19 expressing long AR polyQ repeats. Funding: MIUR project "Dipartimenti di Eccellenza 2018-2020" to Department of Medical Biotechnologies University of Siena, Italy (Italian D.L. n.18 March 17, 2020) and "Bando Ricerca COVID-19 Toscana" project to Azienda Ospedaliero-Universitaria Senese. Private donors for COVID-19 research and charity funds from Intesa San Paolo.
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It is part of: EBioMedicine, 2021, vol. 65
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Appears in Collections:Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

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