Shorter androgen receptor polyQ alleles protect against life-threatening COVID-19 disease in European males

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. We compared poly-amino acids variability from WES data in severely affected COVID-19 patients versus SARS-CoV-2 PCR-positi...

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Detalles Bibliográficos
Autores: Baldassarri, Margherita, Picchiotti, Nicola, Fava, Francesca, Fallerini, Chiara, Benetti, Elisa|||0000-0002-0819-604X, Daga, Sergio, Valentino, Floriana, Doddato, Gabriella, Furini, Simone, Giliberti, Annarita, Tita, Rossella, Amitrano, Sara, Bruttini, Mirella, Croci, Susanna, Meloni, Ilaria, Pinto, Anna Maria|||0000-0001-6259-6901, Iuso, Nicola, Gabbi, Chiara|||0000-0002-9764-4771, Sciarra, Francesca, Venneri, Mary Anna, Gori, Marco, Sanarico, Maurizio, Crawley, Francis P., Pagotto, Uberto, Fanelli, Flaminia, Mezzullo, Marco, Domínguez-Garrido, Elena|||0000-0002-2066-0511, Planas-Serra, Laura|||0000-0002-2586-0897, Schlüter, Agatha|||0000-0001-6732-1528, Colobrán Oriol, Roger|||0000-0002-5964-536X, Soler-Palacín, Pere|||0000-0002-0346-5570, Lapunzina, Pablo|||0000-0002-6324-4825, Tenorio, Jair|||0000-0002-5308-2316, Pujol, Aurora|||0000-0002-9606-0600, Castagna, Maria Grazia, Marcelli, Marco, Isidori, Andrea M.|||0000-0002-9037-5417, Renieri, Alessandra|||0000-0002-0846-9220, Frullanti, Elisa, Mari, Francesca
Tipo de recurso: artículo
Fecha de publicación:2021
País:España
Institución:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:237375
Acceso en línea:https://ddd.uab.cat/record/237375
https://dx.doi.org/urn:doi:10.1016/j.ebiom.2021.103246
Access Level:acceso abierto
Palabra clave:Androgen receptor gene
Testosterone
COVID-19
LASSO logistic regression
WES
Viral infection and host genome
Descripción
Sumario: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. We compared poly-amino acids variability from WES data in severely affected COVID-19 patients versus SARS-CoV-2 PCR-positive oligo-asymptomatic subjects. 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). 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. 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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