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

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; Francesca Mari; Francesca Montagnani; Laura Di Sarno; Andrea Tommasi; Maria Palmieri; Massimiliano Fabbiani; Barbara Rossetti; Giacomo Zanelli; Fausta Sestini; Laura Bergantini; Miriana D'Alessandro; Paolo Cameli; David Bennett; Federico Anedda; Simona Marcantonio; Sabino Scolletta; Federico Franchi; Maria Antonietta Mazzei; Susanna Guerrini; Edoardo Conticini; Luca Cantarini; Bruno Frediani; Danilo Tacconi; Chiara Spertilli; Marco Feri; Alice Donati; Raffaele Scala; Luca Guidelli; Genni Spargi; Marta Corridi; Cesira Nencioni; Leonardo Croci; Gian Piero Caldarelli; Maurizio Spagnesi; Paolo Piacentini; Maria Bandini; Elena Desanctis; Silvia Cappelli; Anna Canaccini; Agnese Verzuri; Valentina Anemoli; Agostino Ognibene; Massimo Vaghi; Antonella D'Arminio Monforte; Esther Merlini; Federica Gaia Miraglia; Mario U. Mondelli; Stefania Mantovani; Serena Ludovisi; Massimo Girardis; Sophie Venturelli; Marco Sita; Andrea Cossarizza; Andrea Antinori; Alessandra Vergori; Arianna Emiliozzi; Stefano Rusconi; Matteo Siano; Arianna Gabrieli; Agostino Riva; Daniela Francisci; Elisabetta Schiaroli; Francesco Paciosi; Pier Giorgio Scotton; Francesca Andretta; Sandro Panese; Stefano Baratti; Renzo Scaggiante; Francesca Gatti; Saverio Giuseppe Parisi; Francesco Castelli; Eugenia Quiros-Roldan; Melania Degli Antoni; Isabella Zanella; Matteo Della Monica; Carmelo Piscopo; Mario Capasso; Roberta Russo; Immacolata Andolfo; Achille Iolascon; Giuseppe Fiorentino; Massimo Carella; Marco Castori; Giuseppe Merla; Filippo Aucella; Pamela Raggi; Carmen Marciano; Rita Perna; Matteo Bassetti; Antonio Di Biagio; Maurizio Sanguinetti; Luca Masucci; Serafina Valente; Maria Antonietta Mencarelli; Caterina Lo Rizzo; Elena Bargagli; Marco Mandalà; Alessia Giorli; Lorenzo Salerni; Patrizia Zucchi; Pierpaolo Parravicini; Elisabetta Menatti; Tullio Trotta; Ferdinando Giannattasio; Gabriella Coiro; Fabio Lena; Domenico A. Coviello; Cristina Mussini; Giancarlo Bosio; Enrico Martinelli; Sandro Mancarella; Luisa Tavecchia; Lia Crotti; Gianfranco Parati; Sergio Aguilera-Albesa; Sergiu Albu; Carlos Casasnovas; Valentina Vélez-Santamaria; Juan Pablo Horcajada; Judit Villar; Agustí Rodríguez-Palmero; Montserrat Ruiz; Luis M. Seijo; Jesús Troya; Juan Valencia-Ramos; Marta Gut

doi:10.1016/j.ebiom.2021.103246

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

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 VenneriMarco 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, Francesca Mari, Francesca Montagnani, Laura Di Sarno, Andrea Tommasi, Maria Palmieri, Massimiliano Fabbiani, Barbara Rossetti, Giacomo Zanelli, Fausta Sestini, Laura Bergantini, Miriana D'Alessandro, Paolo Cameli, David Bennett, Federico Anedda, Simona Marcantonio, Sabino Scolletta, Federico Franchi, Maria Antonietta Mazzei, Susanna Guerrini, Edoardo Conticini, Luca Cantarini, Bruno Frediani, Danilo Tacconi, Chiara Spertilli, Marco Feri, Alice Donati, Raffaele Scala, Luca Guidelli, Genni Spargi, Marta Corridi, Cesira Nencioni, Leonardo Croci, Gian Piero Caldarelli, Maurizio Spagnesi, Paolo Piacentini, Maria Bandini, Elena Desanctis, Silvia Cappelli, Anna Canaccini, Agnese Verzuri, Valentina Anemoli, Agostino Ognibene, Massimo Vaghi, Antonella D'Arminio Monforte, Esther Merlini, Federica Gaia Miraglia, Mario U. Mondelli, Stefania Mantovani, Serena Ludovisi, Massimo Girardis, Sophie Venturelli, Marco Sita, Andrea Cossarizza, Andrea Antinori, Alessandra Vergori, Arianna Emiliozzi, Stefano Rusconi, Matteo Siano, Arianna Gabrieli, Agostino Riva, Daniela Francisci, Elisabetta Schiaroli, Francesco Paciosi, Pier Giorgio Scotton, Francesca Andretta, Sandro Panese, Stefano Baratti, Renzo Scaggiante, Francesca Gatti, Saverio Giuseppe Parisi, Francesco Castelli, Eugenia Quiros-Roldan, Melania Degli Antoni, Isabella Zanella, Matteo Della Monica, Carmelo Piscopo, Mario Capasso, Roberta Russo, Immacolata Andolfo, Achille Iolascon, Giuseppe Fiorentino, Massimo Carella, Marco Castori, Giuseppe Merla, Filippo Aucella, Pamela Raggi, Carmen Marciano, Rita Perna, Matteo Bassetti, Antonio Di Biagio, Maurizio Sanguinetti, Luca Masucci, Serafina Valente, Maria Antonietta Mencarelli, Caterina Lo Rizzo, Elena Bargagli, Marco Mandalà, Alessia Giorli, Lorenzo Salerni, Patrizia Zucchi, Pierpaolo Parravicini, Elisabetta Menatti, Tullio Trotta, Ferdinando Giannattasio, Gabriella Coiro, Fabio Lena, Domenico A. Coviello, Cristina Mussini, Giancarlo Bosio, Enrico Martinelli, Sandro Mancarella, Luisa Tavecchia, Lia Crotti, Gianfranco Parati, Sergio Aguilera-Albesa, Sergiu Albu, Carlos Casasnovas, Valentina Vélez-Santamaria, Juan Pablo Horcajada, Judit Villar, Agustí Rodríguez-Palmero, Montserrat Ruiz, Luis M. Seijo, Jesús Troya, Juan Valencia-Ramos, Marta Gut

Research output: Contribution to journal › Article

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.

Original language	English
Pages (from-to)	103246-103254
Number of pages	9
Journal	EBioMedicine
Volume	65
DOIs	https://doi.org/10.1016/j.ebiom.2021.103246
Publication status	Published - 2021

Keywords

Androgen receptor gene
COVID-19
LASSO logistic regression
Testosterone
Viral infection and host genome
WES

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.ebiom.2021.103246

Cite this

Baldassarri, M., Picchiotti, N., Fava, F., Fallerini, C., Benetti, E., Daga, S., Valentino, F., Doddato, G., Furini, S., Giliberti, A., Tita, R., Amitrano, S., Bruttini, M., Croci, S., Meloni, I., Pinto, A. M., Iuso, N., Gabbi, C., Sciarra, F., ... Gut, M. (2021). Shorter androgen receptor polyQ alleles protect against life-threatening COVID-19 disease in European males. EBioMedicine, 65, 103246-103254. https://doi.org/10.1016/j.ebiom.2021.103246

@article{fbee6d07c54840bca445462d6e521245,

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

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.",

keywords = "Androgen receptor gene, COVID-19, LASSO logistic regression, Testosterone, Viral infection and host genome, WES, Androgen receptor gene, COVID-19, LASSO logistic regression, Testosterone, Viral infection and host genome, WES",

author = "Margherita Baldassarri and Nicola Picchiotti and Francesca Fava and Chiara Fallerini and Elisa Benetti and Sergio Daga and Floriana Valentino and Gabriella Doddato and Simone Furini and Annarita Giliberti and Rossella Tita and Sara Amitrano and Mirella Bruttini and Susanna Croci and Ilaria Meloni and Pinto, {Anna Maria} and Nicola Iuso and Chiara Gabbi and Francesca Sciarra and Venneri, {Mary Anna} and Marco Gori and Maurizio Sanarico and Crawley, {Francis P.} and Uberto Pagotto and Flaminia Fanelli and Marco Mezzullo and Elena Dominguez-Garrido and Laura Planas-Serra and Agatha Schl{\"u}ter and Roger Colobran and Pere Soler-Palacin and Pablo Lapunzina and Jair Tenorio and Aurora Pujol and Castagna, {Maria Grazia} and Marco Marcelli and Isidori, {Andrea M.} and Alessandra Renieri and Elisa Frullanti and Francesca Mari and Francesca Montagnani and {Di Sarno}, Laura and Andrea Tommasi and Maria Palmieri and Massimiliano Fabbiani and Barbara Rossetti and Giacomo Zanelli and Fausta Sestini and Laura Bergantini and Miriana D'Alessandro and Paolo Cameli and David Bennett and Federico Anedda and Simona Marcantonio and Sabino Scolletta and Federico Franchi and Mazzei, {Maria Antonietta} and Susanna Guerrini and Edoardo Conticini and Luca Cantarini and Bruno Frediani and Danilo Tacconi and Chiara Spertilli and Marco Feri and Alice Donati and Raffaele Scala and Luca Guidelli and Genni Spargi and Marta Corridi and Cesira Nencioni and Leonardo Croci and Caldarelli, {Gian Piero} and Maurizio Spagnesi and Paolo Piacentini and Maria Bandini and Elena Desanctis and Silvia Cappelli and Anna Canaccini and Agnese Verzuri and Valentina Anemoli and Agostino Ognibene and Massimo Vaghi and Monforte, {Antonella D'Arminio} and Esther Merlini and Miraglia, {Federica Gaia} and Mondelli, {Mario U.} and Stefania Mantovani and Serena Ludovisi and Massimo Girardis and Sophie Venturelli and Marco Sita and Andrea Cossarizza and Andrea Antinori and Alessandra Vergori and Arianna Emiliozzi and Stefano Rusconi and Matteo Siano and Arianna Gabrieli and Agostino Riva and Daniela Francisci and Elisabetta Schiaroli and Francesco Paciosi and Scotton, {Pier Giorgio} and Francesca Andretta and Sandro Panese and Stefano Baratti and Renzo Scaggiante and Francesca Gatti and Parisi, {Saverio Giuseppe} and Francesco Castelli and Eugenia Quiros-Roldan and Antoni, {Melania Degli} and Isabella Zanella and Monica, {Matteo Della} and Carmelo Piscopo and Mario Capasso and Roberta Russo and Immacolata Andolfo and Achille Iolascon and Giuseppe Fiorentino and Massimo Carella and Marco Castori and Giuseppe Merla and Filippo Aucella and Pamela Raggi and Carmen Marciano and Rita Perna and Matteo Bassetti and {Di Biagio}, Antonio and Maurizio Sanguinetti and Luca Masucci and Serafina Valente and Mencarelli, {Maria Antonietta} and {Lo Rizzo}, Caterina and Elena Bargagli and Marco Mandal{\`a} and Alessia Giorli and Lorenzo Salerni and Patrizia Zucchi and Pierpaolo Parravicini and Elisabetta Menatti and Tullio Trotta and Ferdinando Giannattasio and Gabriella Coiro and Fabio Lena and Coviello, {Domenico A.} and Cristina Mussini and Giancarlo Bosio and Enrico Martinelli and Sandro Mancarella and Luisa Tavecchia and Lia Crotti and Gianfranco Parati and Sergio Aguilera-Albesa and Sergiu Albu and Carlos Casasnovas and Valentina V{\'e}lez-Santamaria and Horcajada, {Juan Pablo} and Judit Villar and Agust{\'i} Rodr{\'i}guez-Palmero and Montserrat Ruiz and Seijo, {Luis M.} and Jes{\'u}s Troya and Juan Valencia-Ramos and Marta Gut",

year = "2021",

doi = "10.1016/j.ebiom.2021.103246",

language = "English",

volume = "65",

pages = "103246--103254",

journal = "EBioMedicine",

issn = "2352-3964",

publisher = "Elsevier B.V.",

}

Baldassarri, M, Picchiotti, N, Fava, F, Fallerini, C, Benetti, E, Daga, S, Valentino, F, Doddato, G, Furini, S, Giliberti, A, Tita, R, Amitrano, S, Bruttini, M, Croci, S, Meloni, I, Pinto, AM, Iuso, N, Gabbi, C, Sciarra, F, Venneri, MA, Gori, M, Sanarico, M, Crawley, FP, Pagotto, U, Fanelli, F, Mezzullo, M, Dominguez-Garrido, E, Planas-Serra, L, Schlüter, A, Colobran, R, Soler-Palacin, P, Lapunzina, P, Tenorio, J, Pujol, A, Castagna, MG, Marcelli, M, Isidori, AM, Renieri, A, Frullanti, E, Mari, F, Montagnani, F, Di Sarno, L, Tommasi, A, Palmieri, M, Fabbiani, M, Rossetti, B, Zanelli, G, Sestini, F, Bergantini, L, D'Alessandro, M, Cameli, P, Bennett, D, Anedda, F, Marcantonio, S, Scolletta, S, Franchi, F, Mazzei, MA, Guerrini, S, Conticini, E, Cantarini, L, Frediani, B, Tacconi, D, Spertilli, C, Feri, M, Donati, A, Scala, R, Guidelli, L, Spargi, G, Corridi, M, Nencioni, C, Croci, L, Caldarelli, GP, Spagnesi, M, Piacentini, P, Bandini, M, Desanctis, E, Cappelli, S, Canaccini, A, Verzuri, A, Anemoli, V, Ognibene, A, Vaghi, M, Monforte, ADA, Merlini, E, Miraglia, FG, Mondelli, MU, Mantovani, S, Ludovisi, S, Girardis, M, Venturelli, S, Sita, M, Cossarizza, A, Antinori, A, Vergori, A, Emiliozzi, A, Rusconi, S, Siano, M, Gabrieli, A, Riva, A, Francisci, D, Schiaroli, E, Paciosi, F, Scotton, PG, Andretta, F, Panese, S, Baratti, S, Scaggiante, R, Gatti, F, Parisi, SG, Castelli, F, Quiros-Roldan, E, Antoni, MD, Zanella, I, Monica, MD, Piscopo, C, Capasso, M, Russo, R, Andolfo, I, Iolascon, A, Fiorentino, G, Carella, M, Castori, M, Merla, G, Aucella, F, Raggi, P, Marciano, C, Perna, R, Bassetti, M, Di Biagio, A, Sanguinetti, M , Masucci, L, Valente, S, Mencarelli, MA, Lo Rizzo, C, Bargagli, E, Mandalà, M, Giorli, A, Salerni, L, Zucchi, P, Parravicini, P, Menatti, E, Trotta, T, Giannattasio, F, Coiro, G, Lena, F, Coviello, DA, Mussini, C, Bosio, G, Martinelli, E, Mancarella, S, Tavecchia, L, Crotti, L, Parati, G, Aguilera-Albesa, S, Albu, S, Casasnovas, C, Vélez-Santamaria, V, Horcajada, JP, Villar, J, Rodríguez-Palmero, A, Ruiz, M, Seijo, LM, Troya, J, Valencia-Ramos, J & Gut, M 2021, 'Shorter androgen receptor polyQ alleles protect against life-threatening COVID-19 disease in European males', EBioMedicine, vol. 65, pp. 103246-103254. https://doi.org/10.1016/j.ebiom.2021.103246

TY - JOUR

T1 - Shorter androgen receptor polyQ alleles protect against life-threatening COVID-19 disease in European males

AU - Baldassarri, Margherita

AU - Picchiotti, Nicola

AU - Fava, Francesca

AU - Fallerini, Chiara

AU - Benetti, Elisa

AU - Daga, Sergio

AU - Valentino, Floriana

AU - Doddato, Gabriella

AU - Furini, Simone

AU - Giliberti, Annarita

AU - Tita, Rossella

AU - Amitrano, Sara

AU - Bruttini, Mirella

AU - Croci, Susanna

AU - Meloni, Ilaria

AU - Pinto, Anna Maria

AU - Iuso, Nicola

AU - Gabbi, Chiara

AU - Sciarra, Francesca

AU - Venneri, Mary Anna

AU - Gori, Marco

AU - Sanarico, Maurizio

AU - Crawley, Francis P.

AU - Pagotto, Uberto

AU - Fanelli, Flaminia

AU - Mezzullo, Marco

AU - Dominguez-Garrido, Elena

AU - Planas-Serra, Laura

AU - Schlüter, Agatha

AU - Colobran, Roger

AU - Soler-Palacin, Pere

AU - Lapunzina, Pablo

AU - Tenorio, Jair

AU - Pujol, Aurora

AU - Castagna, Maria Grazia

AU - Marcelli, Marco

AU - Isidori, Andrea M.

AU - Renieri, Alessandra

AU - Frullanti, Elisa

AU - Mari, Francesca

AU - Montagnani, Francesca

AU - Di Sarno, Laura

AU - Tommasi, Andrea

AU - Palmieri, Maria

AU - Fabbiani, Massimiliano

AU - Rossetti, Barbara

AU - Zanelli, Giacomo

AU - Sestini, Fausta

AU - Bergantini, Laura

AU - D'Alessandro, Miriana

AU - Cameli, Paolo

AU - Bennett, David

AU - Anedda, Federico

AU - Marcantonio, Simona

AU - Scolletta, Sabino

AU - Franchi, Federico

AU - Mazzei, Maria Antonietta

AU - Guerrini, Susanna

AU - Conticini, Edoardo

AU - Cantarini, Luca

AU - Frediani, Bruno

AU - Tacconi, Danilo

AU - Spertilli, Chiara

AU - Feri, Marco

AU - Donati, Alice

AU - Scala, Raffaele

AU - Guidelli, Luca

AU - Spargi, Genni

AU - Corridi, Marta

AU - Nencioni, Cesira

AU - Croci, Leonardo

AU - Caldarelli, Gian Piero

AU - Spagnesi, Maurizio

AU - Piacentini, Paolo

AU - Bandini, Maria

AU - Desanctis, Elena

AU - Cappelli, Silvia

AU - Canaccini, Anna

AU - Verzuri, Agnese

AU - Anemoli, Valentina

AU - Ognibene, Agostino

AU - Vaghi, Massimo

AU - Monforte, Antonella D'Arminio

AU - Merlini, Esther

AU - Miraglia, Federica Gaia

AU - Mondelli, Mario U.

AU - Mantovani, Stefania

AU - Ludovisi, Serena

AU - Girardis, Massimo

AU - Venturelli, Sophie

AU - Sita, Marco

AU - Cossarizza, Andrea

AU - Antinori, Andrea

AU - Vergori, Alessandra

AU - Emiliozzi, Arianna

AU - Rusconi, Stefano

AU - Siano, Matteo

AU - Gabrieli, Arianna

AU - Riva, Agostino

AU - Francisci, Daniela

AU - Schiaroli, Elisabetta

AU - Paciosi, Francesco

AU - Scotton, Pier Giorgio

AU - Andretta, Francesca

AU - Panese, Sandro

AU - Baratti, Stefano

AU - Scaggiante, Renzo

AU - Gatti, Francesca

AU - Parisi, Saverio Giuseppe

AU - Castelli, Francesco

AU - Quiros-Roldan, Eugenia

AU - Antoni, Melania Degli

AU - Zanella, Isabella

AU - Monica, Matteo Della

AU - Piscopo, Carmelo

AU - Capasso, Mario

AU - Russo, Roberta

AU - Andolfo, Immacolata

AU - Iolascon, Achille

AU - Fiorentino, Giuseppe

AU - Carella, Massimo

AU - Castori, Marco

AU - Merla, Giuseppe

AU - Aucella, Filippo

AU - Raggi, Pamela

AU - Marciano, Carmen

AU - Perna, Rita

AU - Bassetti, Matteo

AU - Di Biagio, Antonio

AU - Sanguinetti, Maurizio

AU - Masucci, Luca

AU - Valente, Serafina

AU - Mencarelli, Maria Antonietta

AU - Lo Rizzo, Caterina

AU - Bargagli, Elena

AU - Mandalà, Marco

AU - Giorli, Alessia

AU - Salerni, Lorenzo

AU - Zucchi, Patrizia

AU - Parravicini, Pierpaolo

AU - Menatti, Elisabetta

AU - Trotta, Tullio

AU - Giannattasio, Ferdinando

AU - Coiro, Gabriella

AU - Lena, Fabio

AU - Coviello, Domenico A.

AU - Mussini, Cristina

AU - Bosio, Giancarlo

AU - Martinelli, Enrico

AU - Mancarella, Sandro

AU - Tavecchia, Luisa

AU - Crotti, Lia

AU - Parati, Gianfranco

AU - Aguilera-Albesa, Sergio

AU - Albu, Sergiu

AU - Casasnovas, Carlos

AU - Vélez-Santamaria, Valentina

AU - Horcajada, Juan Pablo

AU - Villar, Judit

AU - Rodríguez-Palmero, Agustí

AU - Ruiz, Montserrat

AU - Seijo, Luis M.

AU - Troya, Jesús

AU - Valencia-Ramos, Juan

AU - Gut, Marta

PY - 2021

Y1 - 2021

N2 - 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.

AB - 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.

KW - Androgen receptor gene

KW - COVID-19

KW - LASSO logistic regression

KW - Testosterone

KW - Viral infection and host genome

KW - WES

KW - Androgen receptor gene

KW - COVID-19

KW - LASSO logistic regression

KW - Testosterone

KW - Viral infection and host genome

KW - WES

UR - http://hdl.handle.net/10807/294256

U2 - 10.1016/j.ebiom.2021.103246

DO - 10.1016/j.ebiom.2021.103246

M3 - Article

SN - 2352-3964

VL - 65

SP - 103246

EP - 103254

JO - EBioMedicine

JF - EBioMedicine

ER -

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

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