Shorter androgen receptor polyQ alleles protect against life-threatening COVID-19 disease in males
Authors: Baldassarri Margherita , Picchiotti Nicola , Fava Francesca , Fallerini Chiara , Benetti Elisa , Daga Sergio , Valentino Floriana , Doddato Gabriella , Furini Simone , Giliberti Annarita , Tita Rossella , Amitrano Sara , Bruttini Mirella , Croci Susanna , Meloni Ilaria , Pinto Anna Maria , Gabbi Chiara , Sciarra Francesca , Venneri Mary Anna , Gori Marco , Sanarico Maurizio , Crawley Francis P. , Pagotto Uberto , Fanelli Flaminia , Mezzullo Marco , Dominguez-Garrido Elena , Planas-Serra Laura , Schlüter Agatha , Colobran Roger , Soler-Palacin Pere , Lapunzina Pablo , Tenorio Jair ,   Spanish Covid HGE, Pujol Aurora , Castagna Maria Grazia , Marcelli Marco , Isidori Andrea M. ,   GEN-COVID Multicenter Study, Renieri Alessandra , Frullanti Elisa , Mari Francesca 
Published: November 2020

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.

Boxes

Evidence before this study

We searched on Medline, EMBASE, and Pubmed for articles published from January 2020 to August 2020 using various combinations of the search terms “sex-difference”, “gender” AND SARS-Cov-2, or COVID. Epidemiological studies indicate that men and women are similarly infected by COVID-19, but the outcome is less favorable in men, independently of age. Several studies also showed that patients with hypogonadism tend to be more severely affected. A prompt intervention directed toward the most fragile subjects with SARS-Cov2 infection is currently the only strategy to reduce mortality. glucocorticoid treatment has been found cost-effective in improving the outcome of severe cases. Clinical algorithms have been proposed, but little is known on the ability of genetic profiling to predict outcome and disclose novel therapeutic strategies.

Added-value of this study

In a cohort of 1178 men and women with COVID-19, we used a supervised machine learning approach on a synthetic representation of the uncovered variability of the human genome due to poly-amino acid repeats. Comparing the genotype of patients with extreme manifestations (severe vs. asymptomatic), we found that the poly-glutamine repeat of the androgen receptor (AR) gene is relevant for COVID-19 disease and defective AR signaling identifies an association between male sex, testosterone exposure, and COVID-19 outcome. Failure of the endocrine feedback to overcome AR signaling defect by increasing testosterone levels during the infection leads to the fact that polyQ becomes dominant to T levels for the clinical outcome.

Implications of all the available evidence

We identify the first genetic polymorphism predisposing some men to develop a more severe disease irrespectively of age. Based on this, we suggest that sizing the AR poly-glutamine repeat has important implications in the diagnostic pipeline of patients affected by life-threatening COVID-19 infection. Most importantly, our studies open to the potential of using testosterone as adjuvant therapy for severe COVID-19 patients having defective androgen signaling, defined by this study as ≥23 PolyQ repeats and inappropriate levels of circulating androgens.