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

Abstract

Background: While SARS-CoV-2 similarly infects men and women, COVID-19 outcome is less favorable in men. Variability in COVID-19 severity may be explained by differences in the host genome.

Methods: We compared poly-amino acids variability from WES data in severely affected COVID-19 patients versus SARS-CoV-2 PCR-positive oligo-asymptomatic subjects.

Findings: Shorter polyQ alleles (≤22) in the androgen receptor (AR) conferred protection against severe outcome in COVID-19 in the first tested cohort (both males and females) of 638 Italian subjects. The association between long polyQ alleles (≥23) and severe clinical outcome (p = 0.024) was also validated in an independent cohort of Spanish men <60 years of age (p = 0.014). Testosterone was higher in subjects with AR long-polyQ, possibly indicating receptor resistance (p = 0.042 Mann-Whitney U test). Inappropriately low serum testosterone level among carriers of the long-polyQ alleles (p = 0.0004 Mann-Whitney U test) 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 and age ≥60 years had increased levels of CRP (p = 0.018, not accounting for multiple testing).

Interpretation: We identify the first genetic polymorphism that appears to predispose some men to develop more severe disease. Failure of the endocrine feedback to overcome AR signaling defects by increasing testosterone levels during the infection leads to the polyQ tract becoming dominant to serum testosterone levels for the clinical outcome. These results may contribute to designing reliable clinical and public health measures and provide a rationale to test testosterone as adjuvant therapy in men with COVID-19 expressing long AR polyQ 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) and "Bando Ricerca COVID-19 Toscana" project to Azienda Ospedaliero-Universitaria Senese. Private donors for COVID-19 research and charity funds from Intesa San Paolo.

Keywords: Androgen receptor gene; COVID-19; LASSO logistic regression; Testosterone; Viral infection and host genome; WES.

Fig. 1

LASSO logistic regression. The bar of the LASSO logistic regression beta coefficients represents the importance of each feature for the classification task (Fig. 1) (Panel a). The positive beta coefficients of the LASSO (upward bars) reflect a susceptible behaviour of the features to the target COVID-19 disease, whereas the negative coefficients (downward bars) a protective action. The calculated odd ratio of AR short repeats (≤22) is 0.79 i.e. protective. Therefore, the odd ratio of long repeats (≥23) is 1/0.79 = 1.27 i.e. severity. Panel b: Table reporting the averages and the standard deviations of accuracy, precision, sensitivity, specificity, and ROC-AUC scores for the 10-folds of the cross-validation.

Fig. 2

Relationship between Total Testosterone and polyQ repeats in the case and the control group. Box-plot showing values of Total Testosterone (TT), expressed in nmol/L, in subjects with shorter (≤22) and longer (≥23) polyQ repeats in AR gene grouped between controls (left panel) and cases (right panel). The TT median value, represented by the black horizontal line, is higher in patients with ≥23 polyQ repeats in the case group, (**p-value = 0.023; Mann-Whitney U test). No statistically significant difference was present in the control group (p-value = 0.088; Mann-Whitney U test).