EBioMedicine (Mar 2021)
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
Affiliations
- Margherita Baldassarri
- Medical Genetics, University of Siena, Italy; Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Italy
- Nicola Picchiotti
- University of Siena, DIISM-SAILAB, Siena, Italy; Department of Mathematics, University of Pavia, Pavia, Italy
- Francesca Fava
- Medical Genetics, University of Siena, Italy; Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Italy; Genetica Medica, Azienda Ospedaliero-Universitaria Senese, Italy
- Chiara Fallerini
- Medical Genetics, University of Siena, Italy; Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Italy
- Elisa Benetti
- Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Italy
- Sergio Daga
- Medical Genetics, University of Siena, Italy; Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Italy
- Floriana Valentino
- Medical Genetics, University of Siena, Italy; Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Italy
- Gabriella Doddato
- Medical Genetics, University of Siena, Italy; Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Italy
- Simone Furini
- Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Italy
- Annarita Giliberti
- Medical Genetics, University of Siena, Italy; Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Italy
- Rossella Tita
- Genetica Medica, Azienda Ospedaliero-Universitaria Senese, Italy
- Sara Amitrano
- Genetica Medica, Azienda Ospedaliero-Universitaria Senese, Italy
- Mirella Bruttini
- Medical Genetics, University of Siena, Italy; Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Italy; Genetica Medica, Azienda Ospedaliero-Universitaria Senese, Italy
- Susanna Croci
- Medical Genetics, University of Siena, Italy; Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Italy
- Ilaria Meloni
- Medical Genetics, University of Siena, Italy; Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Italy
- Anna Maria Pinto
- Genetica Medica, Azienda Ospedaliero-Universitaria Senese, Italy
- Nicola Iuso
- Medical Genetics, University of Siena, Italy; Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Italy
- Chiara Gabbi
- Independent Medical Scientist, Milan, Italy
- Francesca Sciarra
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
- Mary Anna Venneri
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
- Marco Gori
- University of Siena, DIISM-SAILAB, Siena, Italy; Université Côte d'Azur, Inria, CNRS, I3S, Maasai
- Maurizio Sanarico
- Independent Data Scientist, Milan, Italy
- Francis P. Crawley
- Good Clinical Practice Alliance-Europe (GCPA) and Strategic Initiative for Developing Capacity in Ethical Review-Europe (SIDCER), Leuven, Belgium
- Uberto Pagotto
- Unit of Endocrinology and Prevention and Care of Diabetes, Center for Applied, Biomedical Research, Department of Medical and Surgical Sciences, University of Bologna, S. Orsola-Malpighi Hospital, Bologna, Italy
- Flaminia Fanelli
- Unit of Endocrinology and Prevention and Care of Diabetes, Center for Applied, Biomedical Research, Department of Medical and Surgical Sciences, University of Bologna, S. Orsola-Malpighi Hospital, Bologna, Italy
- Marco Mezzullo
- Unit of Endocrinology and Prevention and Care of Diabetes, Center for Applied, Biomedical Research, Department of Medical and Surgical Sciences, University of Bologna, S. Orsola-Malpighi Hospital, Bologna, Italy
- Elena Dominguez-Garrido
- Molecular Diagnostic Unit, Fundación Rioja Salud, Logroño, La Rioja, Spain
- Laura Planas-Serra
- Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain; CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, Melchor Fernández Almagro, 3, 28029 Madrid, Spain; Spanish Covid HGE
- Agatha Schlüter
- Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain; CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, Melchor Fernández Almagro, 3, 28029 Madrid, Spain; Spanish Covid HGE
- Roger Colobran
- Immunology Division, Genetics Department, Hospital Universitari Vall d'Hebron, Vall d'Hebron Research Institute, Vall d'Hebron Barcelona Hospital Campus, Universitat Autònoma de Barcelona (UAB), Barcelona, Catalonia, Spain, EU
- Pere Soler-Palacin
- Pediatric Infectious Diseases and Immunodeficiencies Unit, Hospital Universitari Vall d'Hebron, Vall d'Hebron Research Institute, Barcelona, Catalonia, Spain
- Pablo Lapunzina
- CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, Melchor Fernández Almagro, 3, 28029 Madrid, Spain; Institute of Medical and Molecular Genetics (INGEMM)-IdiPAZ, Hospital Universitario La Paz-UAM Paseo de La Castellana, 261, 28046 Madrid, Spain
- Jair Tenorio
- CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, Melchor Fernández Almagro, 3, 28029 Madrid, Spain; Institute of Medical and Molecular Genetics (INGEMM)-IdiPAZ, Hospital Universitario La Paz-UAM Paseo de La Castellana, 261, 28046 Madrid, Spain
- Aurora Pujol
- Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain; CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, Melchor Fernández Almagro, 3, 28029 Madrid, Spain; Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain
- Maria Grazia Castagna
- Department of Medical, Surgical and Neurological Sciences, University of Siena, Italy
- Marco Marcelli
- Department of Medicine, Baylor College of Medicine, Houston TX, USA
- Andrea M. Isidori
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
- Alessandra Renieri
- Medical Genetics, University of Siena, Italy; Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Italy; Genetica Medica, Azienda Ospedaliero-Universitaria Senese, Italy; Corresponding author.
- Elisa Frullanti
- Medical Genetics, University of Siena, Italy; Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Italy
- Francesca Mari
- Medical Genetics, University of Siena, Italy; Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Italy; Genetica Medica, Azienda Ospedaliero-Universitaria Senese, Italy
- Journal volume & issue
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Vol. 65
p. 103246
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.
