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

Medical Genetics, University of Siena, Italy; Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Italy. University of Siena, DIISM-SAILAB, Siena, Italy; Department of Mathematics, University of Pavia, Pavia, Italy. 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. Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Italy. Genetica Medica, Azienda Ospedaliero-Universitaria Senese, Italy. Independent Medical Scientist, Milan, Italy. Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy. University of Siena, DIISM-SAILAB, Siena, Italy; Université Côte d'Azur, Inria, CNRS, I3S, Maasai. Independent Data Scientist, Milan, Italy. Good Clinical Practice Alliance-Europe (GCPA) and Strategic Initiative for Developing Capacity in Ethical Review-Europe (SIDCER), Leuven, Belgium. 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. Molecular Diagnostic Unit, Fundación Rioja Salud, Logroño, La Rioja, Spain. 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. 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. Pediatric Infectious Diseases and Immunodeficiencies Unit, Hospital Universitari Vall d'Hebron, Vall d'Hebron Research Institute, Barcelona, Catalonia, Spain. 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. 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. Department of Medical, Surgical and Neurological Sciences, University of Siena, Italy. Department of Medicine, Baylor College of Medicine, Houston TX, USA. 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. Electronic address: alessandra.renieri@unisi.it.

EBioMedicine. 2021;:103246
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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.