Background COVID-19 MESHD
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 MESHD infected MESHD
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 HGNC
(AR) conferred protection against a more severe outcome in COVID-19 MESHD
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 MESHD
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 HGNC
(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 MESHD
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.