Shorter Androgen Receptor PolyQ Alleles Protect Against Life-Threatening COVID-19 Disease in Males

Baldassarri, Margherita; Missale, Francesco; 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; Gori, Marco; Sanarico, Maurizio; Crawley, Francis P.; Castagna, Maria Grazia; Marcelli, Marco; Isidori, Andrea M.; Study, Gen-Covid Multicenter; Renieri, Alessandra; Frullanti, Elisa; Mari, Francesca

doi:10.2139/ssrn.3692488

Cited by 8 publications

(7 citation statements)

References 19 publications

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“…Authors also observed that longer polyQ alleles are associated with higher serum testosterone levels, most likely due to impairment of negative feedback of the HPT axis. This study concluded an individual's 'androgenicity', itself being a function of polyQ status and serum testosterone levels, may be protective against severe Covid‐19 46 …”

Section: Endogenous Testosterone and Covid‐19 Morbidity And Mortalitymentioning

confidence: 82%

Men, testosterone and Covid‐19

Groti Antonic,

Antonic,

Caliber

et al. 2023

Clinical Endocrinology

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Men have more severe Coronavirus disease 2019 (Covid‐19) outcomes and higher mortality rates than women, and it was suggested that testosterone levels might promote severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection and Covid‐19 severity. However, clinical studies have not supported this theory. Studies have consistently shown that serum testosterone concentrations during acute Covid‐19 in men are inversely proportional to the inflammatory cytokines and severity of illness. It is likely that lower testosterone concentrations in this setting are a result of acute Covid‐19 illness on the hypothalamic–pituitary–testicular axis. Clinical trials that attempted to lower testosterone concentrations further or block androgen signaling acutely during Covid‐19 in men did not result in improved Covid‐19 outcomes. Additionally, pre‐existing male hypogonadism, diagnosed before Covid‐19 pandemic, was found to be a risk factor for hospitalization from Covid‐19. In this review, we also discuss the preclinical and mechanistic studies that have evaluated the role of androgens in SARS‐CoV‐2 infection and illness. Finally, long‐term consequences of Covid‐19 on male reproductive health are reviewed. SARS‐CoV‐2 virus is known to infiltrate testis and induce orchitis in men, but it is unclear if Covid‐19 leads to an increase in incidence of male hypogonadism.

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Section: Endogenous Testosterone and Covid‐19 Morbidity And Mortalitymentioning

confidence: 82%

Men, testosterone and Covid‐19

Groti Antonic,

Antonic,

Caliber

et al. 2023

Clinical Endocrinology

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“…In order to understand the biological basis of hypogonadism and its correlation to Covid‐19 severity, Baldassarri et al. (2021) focussed on the role of AR polymorphisms 66 . The X‐linked AR gene is characterised by a highly polymorphic poly glutamine (polyQ) tract at its N‐terminus, which may have 9 to 36 glutamine coding CAG repeats, with 20 repeats having the highest frequency in humans 67 .…”

Section: Testosterone and Covid‐19 Severitymentioning

confidence: 99%

“…In a nested case‐control study of 638 male and female Covid‐19 patients, Baldassarri et al. (2021) observed that shorter polyQ tracts (<22) which would have higher AR functionality was protective of worse clinical outcomes in individuals of <60 years 66 . The authors also show that the longer polyQ tracts (>23) are associated with higher serum T levels, possibly due to a dysregulation in hypothalamo‐pituitary negative feedback, and an increased pro‐inflammatory status 66 .…”

Section: Testosterone and Covid‐19 Severitymentioning

confidence: 99%

“…(2021) observed that shorter polyQ tracts (<22) which would have higher AR functionality was protective of worse clinical outcomes in individuals of <60 years 66 . The authors also show that the longer polyQ tracts (>23) are associated with higher serum T levels, possibly due to a dysregulation in hypothalamo‐pituitary negative feedback, and an increased pro‐inflammatory status 66 . Taken together, their study suggests that the risk of disease severity can be predicted by the ‘androgenicity’ of the individual which is a function of polyQ status and their serum T levels.…”

Section: Testosterone and Covid‐19 Severitymentioning

confidence: 99%

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Testosterone and Covid‐19: An update

Yassin

Sabsigh

Al‐Zoubi

et al. 2022

Reviews in Medical Virology

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There is overwhelming evidence to suggest that male gender is at a higher risk of developing more severe Covid-19 disease and thus having poorer clinical outcomes.However, the relationship between testosterone (T) and Covid-19 remains unclear with both protective and deleterious effects on different aspects of the disease suggested. Here, we review the current epidemiological and biological evidence on the role of testosterone in the process of SARS-CoV-2 infection and in mediating Covid-19 severity, its potential to serve as a biomarker for risk stratification and discuss the possibility of T supplementation as a treatment or preventative therapy for Covid-19. K E Y W O R D Sprostate, sexual medicine, testosterone | INTRODUCTIONSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2, also known as Corona Virus Disease 2019 or Covid-19) exhibits differences in morbidity and mortality between sexes, with a male bias towards severe disease. [1][2][3][4] A meta-analysis of over 3 million cases globally (accumulated from 92 data sets that contained information on the total number of infections by sex, and the severity of disease as measured by admission to intensive therapy unit (ITU) and death) has shown that whilst there are no sex-based differences in the proportion of Covid-19 cases, male patients have higher odds for requiring Intensive treatment (odds ratio OR = 2.84) and death (OR = 1.39) compared to females, despite this analysis not controlling for lifestyle, comorbidities, testing method and case type (hospital vs. community). 5 This sex difference is apparent across different countries when comparing Covid-19 fatality (Figure 1). 6 Epidemiological data from the previous coronavirus epidemic of SARS-CoV (2002) also show preponderancy of poorer outcomes forThis is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

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“…a LASSO logistic regression, has been applied to extract some thousands of coding genetic features contributing to COVID-19 severity [35, 16]. Subsequent functional validation of extracted features demonstrated that, in each tested case, the association with severity has a biological basis and suggested hints for adjuvant treatment [5, 15, 14, 11, 3, 2, 27, 31]. Using the extracted features it has been built a severity score named Integrated PolyGenic Score (IPGS), whose performances reached about 75% for both sensitivity and specificity [16].…”

Section: Introductionmentioning

confidence: 99%

Host genetics and COVID-19 severity: increasing the accuracy of latest severity scores by Boolean quantum features

Martelloni

Turchi

Fallerini

et al. 2023

Preprint

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The impact of common and rare variants in COVID-19 host genetics is widely studied in [16]. Here, common and rare variants were used to define an interpretable machine learning model for predicting COVID-19 severity. Firstly, variants were converted into sets of Boolean features, depending on the absence or the presence of variants in each gene. An ensemble of LASSO logistic regression models was used to identify the most informative Boolean features with respect to the genetic bases of severity. After that, the Boolean features, selected by these logistic models, were combined into an Integrated PolyGenic Score, the so called IPGS, which offers a very simple description of the contribution of host genetics in COVID-19 severity. IPGS leads to an accuracy of 55-60% on different cohorts and, after a logistic regression with in input both IPGS and the age, it leads to an accuracy of 75%. The goal of this paper is to improve the previous results, using the information on the host organs involved in the disease. We generalized the IPGS adding a statistical weight for each organ, through the transformation of Boolean features into "Boolean quantum features", inspired by the Quantum Mechanics. The organs' coefficients were set via the application of the genetic algorithm Pygad and, after that, we defined two new Integrated PolyGenic Score (IPGS1 and IPGS2). By applying a logistic regression with both IPGS2 (or indifferently IPGS1) and age as input, we reach an accuracy of 84-86%, thus improving the results previously shown in [16] by a factor of 10%.

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Shorter Androgen Receptor PolyQ Alleles Protect Against Life-Threatening COVID-19 Disease in Males

Cited by 8 publications

References 19 publications

Men, testosterone and Covid‐19

Men, testosterone and Covid‐19

Testosterone and Covid‐19: An update

Host genetics and COVID-19 severity: increasing the accuracy of latest severity scores by Boolean quantum features

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