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 is due in part to specific mutations in the host genome. GWAS effectively identifies genetic variability due to common biallelic polymorphisms. Efforts in genetic research are trying to identify significant associations in patients infected by SARS-CoV-2. 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 might explain disease severity due to rare variants and poly-amino acids repeat polymorphisms. Using host whole-exome sequencing data, we compared extreme phenotypic presentations of an Italian cohort of 939 subjects infected with SARS-CoV-2. We then applied the LASSO Logistic Regression model on Boolean gene-based representation of the entire set of human genes. Findings: Polymorphisms/rare variants in certain genes, including short polyQ (≤22) of the androgen receptor ( AR ), conferred protection against severe forms of COVID-19. We then demonstrated that testosterone was higher in males with AR long-polyQ (≥23), confirming receptor resistance (p=0.004 Mann-Whitney U test). Finally, long-polyQ (≥23) correlates with increased inflammation markers (p=0.021) and fibrinogen consumption (p=0.039), confirming the anti-inflammatory role of testosterone. Interpretation: Our results contribute to designing reliable clinical and public health measures and provide a rationale to test testosterone supplementation as adjuvant treatment in symptomatic COVID-19 men expressing AR polyQ longer than 23. Funding: MIUR project “Dipartimenti di Eccellenza 2018-2020” to Department of Medical Biotechnologies University of Siena, Italy; Private donors for COVID research (Italian D.L. n.18 March 17, 2020).Declaration of Interests: The authors declare no competing interests.Ethics Approval Statement: The GEN-COVID study was approved by the University Hospital of Siena Ethics Review Board (Protocol n. 16917, dated March 16, 2020).