Shorter androgen receptor polyQ alleles protect against life-threatening COVID-19 disease in European males
Baldassarri, Margherita (University of Siena. Department of Medical Biotechnologies)
Picchiotti, Nicola (University of Pavia. Department of Mathematics)
Fava, Francesca (Azienda Ospedaliero-Universitaria Senese (Itàlia))
Fallerini, Chiara (University of Siena. Department of Medical Biotechnologies)
Benetti, Elisa (University of Siena. Department of Medical Biotechnologies)
Daga, Sergio (University of Siena. Department of Medical Biotechnologies)
Valentino, Floriana (University of Siena. Department of Medical Biotechnologies)
Doddato, Gabriella (University of Siena. Department of Medical Biotechnologies)
Furini, Simone (University of Siena. Department of Medical Biotechnologies)
Giliberti, Annarita (University of Siena. Department of Medical Biotechnologies)
Tita, Rossella (Azienda Ospedaliero-Universitaria Senese (Itàlia))
Amitrano, Sara (Azienda Ospedaliero-Universitaria Senese (Itàlia))
Bruttini, Mirella (Azienda Ospedaliero-Universitaria Senese (Itàlia))
Croci, Susanna (University of Siena. Department of Medical Biotechnologies)
Meloni, Ilaria (University of Siena. Department of Medical Biotechnologies)
Pinto, Anna Maria (Azienda Ospedaliero-Universitaria Senese (Itàlia))
Iuso, Nicola (University of Siena. Department of Medical Biotechnologies)
Gabbi, Chiara
Sciarra, Francesca (Sapienza University of Rome. Department of Experimental Medicine)
Venneri, Mary Anna (Sapienza University of Rome. Department of Experimental Medicine)
Gori, Marco (Université Côte d'Azur)
Sanarico, Maurizio
Crawley, Francis P. (Good Clinical Practice Alliance-Europe (GCPA) and Strategic Initiative for Developing Capacity in Ethical Review-Europe (SIDCER) (Leuven, Bèlgica))
Pagotto, Uberto (University of Bologna. Department of Medical and Surgical Sciences)
Fanelli, Flaminia (University of Bologna. Department of Medical and Surgical Sciences)
Mezzullo, Marco (University of Bologna. Department of Medical and Surgical Sciences)
Domínguez-Garrido, Elena (Fundación Rioja Salud. Molecular Diagnostic Unit)
Planas-Serra, Laura (Spanish Covid HGE)
Schlüter, Agatha (Spanish Covid HGE)
Colobrán Oriol, Roger (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Soler-Palacín, Pere (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Lapunzina, Pablo (Hospital Universitario La Paz (Madrid))
Tenorio, Jair (Hospital Universitario La Paz (Madrid))
Pujol, Aurora 1968- (Institució Catalana de Recerca i Estudis Avançats)
Castagna, Maria Grazia (University of Siena. Department of Medical, Surgical and Neurological Sciences)
Marcelli, Marco (Baylor College of Medicine (Houston, Estats Units d'Amèrica). Department of Medicine)
Isidori, Andrea M. (Sapienza University of Rome. Department of Experimental Medicine)
Renieri, Alessandra (Azienda Ospedaliero-Universitaria Senese (Itàlia))
Frullanti, Elisa (University of Siena. Department of Medical, Surgical and Neurological Sciences)
Mari, Francesca (Azienda Ospedaliero-Universitaria Senese (Itàlia))
Universitat Autònoma de Barcelona

Data:	2021
Resum:	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.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Androgen receptor gene ; Testosterone ; COVID-19 ; LASSO logistic regression ; WES ; Viral infection and host genome
Publicat a:	EBioMedicine, Vol. 65 (february 2021) , p. 103246, ISSN 2352-3964

DOI: 10.1016/j.ebiom.2021.103246
PMID: 33647767

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