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

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.; Gabbi, C.; Sciarra, F.; Venneri, M. A.; Gori, M.; Sanarico, M.; Crawley, F. P.; Pagotto, U.; Fanelli, F.; Mezzullo, M.; Dominguez-Garrido, E.; Planas-Serra, L.; Schluter, A.; Colobran, R.; Soler-Palacin, P.; Lapunzina, P.; Tenorio, J.; Spanish Covid HGE,; Pujol, A.; Castagna, M. G.; Marcelli, M.; Isidori, A. M.; GEN-COVID Multicenter Study,; Renieri, A.; Frullanti, E.; Mari, F.

Background COVID-19 presentation ranges from asymptomatic to fatal. The variability in severity may be due in part to impaired Interferon type I response due to specific mutations in the host genome or to autoantibodies, explaining about 15% of the cases when combined. Exploring the host genome is thus warranted to further elucidate disease variability. Methods We developed a synthetic approach to genetic data representation using machine learning methods to investigate complementary genetic variability in COVID-19 infected patients that may explain disease severity, due to poly-amino acids repeat polymorphisms. Using host whole-exome sequencing data, we compared extreme phenotypic presentations (338 severe versus 300 asymptomatic cases) of the entire (men and women) Italian GEN-COVID cohort of 1178 subjects infected with SARS-CoV-2. We then applied the LASSO Logistic Regression model on Boolean gene-based representation of the poly-amino acids variability. Findings Shorter polyQ alleles ([≤]22) in the androgen receptor (AR) conferred protection against a more severe outcome in COVID-19 infection. In the subgroup of males with age <60 years, testosterone was higher in subjects with AR long-polyQ ([≥]23), possibly indicating receptor resistance (p=0.004 Mann-Whitney U test). Inappropriately low testosterone levels for the long-polyQ alleles 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 ([≥]23) and age>60 years had increased levels of C Reactive Protein (p=0.018). Interpretation Our results may contribute to design reliable clinical and public health measures and provide a rationale to test testosterone treatment as adjuvant therapy in symptomatic COVID-19 men expressing AR polyQ longer than 23 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). Private donors for COVID research and charity funds from Intesa San Paolo.