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

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 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.