Shorter androgen receptor polyQ alleles protect against life-threatening COVID-19 disease in European males
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...
| Autores: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Tipo de recurso: | artículo |
| Fecha de publicación: | 2021 |
| País: | España |
| Institución: | Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
| Repositorio: | Recercat. Dipósit de la Recerca de Catalunya |
| OAI Identifier: | oai:recercat.cat:2445/176821 |
| Acceso en línea: | https://hdl.handle.net/2445/176821 |
| Access Level: | acceso abierto |
| Palabra clave: | Andrògens COVID-19 Testosterona Androgens Testosterone |
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Shorter androgen receptor polyQ alleles protect against life-threatening COVID-19 disease in European malesBaldassarri, MargheritaPicchiotti, NicolaFava, FrancescaFallerini, ChiaraBenetti, ElisaDaga, SergioValentino, FlorianaDoddato, GabriellaFurini, SimoneGiliberti, AnnaritaTita, RossellaAmitrano, SaraBruttini, MirellaCroci, SusannaMeloni, IlariaPinto, Anna MariaIuso, NicolaGabbi, ChiaraSciarra, FrancescaVenneri, Mary AnnaGori, MarcoSanarico, MaurizioCrawley, Francis P.Pagotto, UbertoFanelli, FlaminiaMezzullo, MarcoDominguez Garrido, ElenaPlanas Serra, LauraSchlüter, AgathaColobran, RogerSoler Palacín, PereLapunzina, PabloTenorio, JairPujol Onofre, AuroraCastagna, Maria GraziaMarcelli, MarcoIsidori, Andrea M.Renieri, AlessandraFrullanti, ElisaMari, FrancescaSpanish Covid HGE, GENCOVID Multicenter StudyAndrògensCOVID-19TestosteronaAndrogensCOVID-19TestosteroneBackground: 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.Elsevier BV2021202120212021info:eu-repo/semantics/article10 p.application/pdfhttps://hdl.handle.net/2445/176821Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésReproducció del document publicat a: https://doi.org/10.1016/j.ebiom.2021.103246EBioMedicine, 2021, vol. 65https://doi.org/10.1016/j.ebiom.2021.103246cc by-nc-nd (c) Baldassarria et al., 2021http://creativecommons.org/licenses/by-nc-nd/3.0/es/info:eu-repo/semantics/openAccessoai:recercat.cat:2445/1768212026-05-29T05:05:01Z |
| dc.title.none.fl_str_mv |
Shorter androgen receptor polyQ alleles protect against life-threatening COVID-19 disease in European males |
| title |
Shorter androgen receptor polyQ alleles protect against life-threatening COVID-19 disease in European males |
| spellingShingle |
Shorter androgen receptor polyQ alleles protect against life-threatening COVID-19 disease in European males Baldassarri, Margherita Andrògens COVID-19 Testosterona Androgens COVID-19 Testosterone |
| title_short |
Shorter androgen receptor polyQ alleles protect against life-threatening COVID-19 disease in European males |
| title_full |
Shorter androgen receptor polyQ alleles protect against life-threatening COVID-19 disease in European males |
| title_fullStr |
Shorter androgen receptor polyQ alleles protect against life-threatening COVID-19 disease in European males |
| title_full_unstemmed |
Shorter androgen receptor polyQ alleles protect against life-threatening COVID-19 disease in European males |
| title_sort |
Shorter androgen receptor polyQ alleles protect against life-threatening COVID-19 disease in European males |
| dc.creator.none.fl_str_mv |
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 |
| author |
Baldassarri, Margherita |
| author_facet |
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 |
| author_role |
author |
| author2 |
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 |
| author2_role |
author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author |
| dc.subject.none.fl_str_mv |
Andrògens COVID-19 Testosterona Androgens COVID-19 Testosterone |
| topic |
Andrògens COVID-19 Testosterona Androgens COVID-19 Testosterone |
| description |
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. |
| publishDate |
2021 |
| dc.date.none.fl_str_mv |
2021 2021 2021 2021 |
| dc.type.none.fl_str_mv |
info:eu-repo/semantics/article |
| format |
article |
| dc.identifier.none.fl_str_mv |
https://hdl.handle.net/2445/176821 |
| url |
https://hdl.handle.net/2445/176821 |
| dc.language.none.fl_str_mv |
Inglés |
| language_invalid_str_mv |
Inglés |
| dc.relation.none.fl_str_mv |
Reproducció del document publicat a: https://doi.org/10.1016/j.ebiom.2021.103246 EBioMedicine, 2021, vol. 65 https://doi.org/10.1016/j.ebiom.2021.103246 |
| dc.rights.none.fl_str_mv |
cc by-nc-nd (c) Baldassarria et al., 2021 http://creativecommons.org/licenses/by-nc-nd/3.0/es/ info:eu-repo/semantics/openAccess |
| rights_invalid_str_mv |
cc by-nc-nd (c) Baldassarria et al., 2021 http://creativecommons.org/licenses/by-nc-nd/3.0/es/ |
| eu_rights_str_mv |
openAccess |
| dc.format.none.fl_str_mv |
10 p. application/pdf |
| dc.publisher.none.fl_str_mv |
Elsevier BV |
| publisher.none.fl_str_mv |
Elsevier BV |
| dc.source.none.fl_str_mv |
Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL)) reponame:Recercat. Dipósit de la Recerca de Catalunya instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
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Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
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Recercat. Dipósit de la Recerca de Catalunya |
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Recercat. Dipósit de la Recerca de Catalunya |
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15.811543 |