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).

Role of testosterone in SARS-CoV-2 infection: A key pathogenic factor and a biomarker for severe pneumonia

“…Interestingly, the androgen receptor is the main activator of transcription of the TMPRSS2 gene in humans (Lucas et al, 2014;Stopsack et al, 2020;Anon, 2020). Accordingly, androgen sensitivity, determined by haplotypes of the androgen receptor and their expressivity, can explain racial and interindividual susceptibility to severe COVID-19 (Baldassarri et al, 2021). This assumption is supported by the observations that androgenetic alopecia, a phenotypic expression of an androgen-dependent trait, seems to predispose to severe COVID-19 symptoms (CDC COVID-19 Response Team, 2020;Wambier et al, 2020), and that the clinical picture of COVID-19 is less severe before puberty (Shi et al, 2020).…”

In response to the letter to the editor by Soha Ghanian et al. re our publication “Shorter androgen receptor polyQ alleles protect against life-threatening COVID-19 disease in European males”

“…In contrast, in AndroCoV, most of the time-to remission outcomes were measured after 7-10 days, when virus clearance plays a minor role and the outcome depends on abnormal immune response and endothelial damage. Our paper [3] explains that at this stage, AR function correlates with a beneficial immune-modulatory effect in patients with increased T, that overcomes receptor resistance. As a consequence, we would not expect clinical effects of testosterone-induced modulation of TMPRSS2 in COVID-19 patients seven or ten days after the onset of symptoms, as shown in a study where androgen deprivation therapy did not protect against SARS-CoV-2 [4] .…”

“…Going along with the concept that AR with longer CAG repeats is less transcriptionally active, we hypothesized that longer CAG repeats are associated with a more aggressive COVID-19 phenotype. In comparison, we think that less aggressive COVID-19 infections result from more active ARs with shorter CAG repeat [3] . McCoy reached the opposite conclusion, that ARs with longer CAG repeats are more active, due to different expressions of coactivators versus corepressors in the lungs.…”

Letter to the Editor re: Baldassarri et al., 2021 “Shorter androgen receptor polyQ alleles protect against life-threatening COVID-19 disease in European males”

“…We would like to thank Baldassarri et al. for presenting their findings that short androgen receptor (AR) polyQ alleles confer protection against life-threatening COVID-19 infection among European males [1] .…”

“…Baldassarri et al. suggested to initiate clinical trials of testosterone therapy in men expressing defective androgen signaling and having serologic evidence of hypoandrogenism [1] . There is evidence that th lower AR activity caused by the longer CAG repeats is biologically compensated by increased testosterone levels.…”