Androgen receptor genetic variant predicts COVID‐19 disease severity: a prospective longitudinal study of hospitalized COVID‐19 male patients

To the Editor,

Men infected with SARS‐CoV‐2 are more likely to be admitted to the intensive care unit (ICU) compared with women. ¹ Previously, we have reported that among hospitalized men with COVID‐19, 79% presented with androgenetic alopecia (AA) compared with 31–53% that would be expected in a similar aged match population. ² AA is known to be mediated by variations in the androgen receptor (AR) gene. ³ In addition, the only known promoter of the enzyme implicated in SARS‐CoV‐2 infectivity, transmembrane protease, serine 2, is regulated by an androgen response element. ⁴ The polyglutamine repeat (CAG repeat) located in the AR gene is associated with androgen sensitivity and AA. ³ These observations led us to hypothesize that variations in the AR gene may predispose male COVID‐19 patients to increased disease severity.

We conducted a prospective longitudinal study of hospitalized COVID‐19 males. The subjects were categorized into two cohorts: subjects with a CAG ≥ 22 and subjects with a CAG < 22. Subjects taking androgen modifying drugs, e.g. 5‐alpha reductase inhibitors, were excluded. DNA was collected using ORAcollect•Dx: (DNA Genotek, Ottawa, ON, Canada). AR CAG repeat region was PCR‐amplified and 300 bp paired‐end sequencing was performed using a MiSeq (Illumina, San Diego, CA, USA). Reads were mapped to referenceAR sequences containing 1–50 CAG repeats, the reference with the greatest number of mapped reads was reported as the CAG repeat count. Subjects were followed for a period of 60 days from the date of hospitalization. Primary and secondary outcomes were the rate of ICU admissions and length of hospitalization, respectively.

Seventy‐seven COVID‐19‐positive men were recruited to the study; 12 were excluded due to their use of androgen modifying drugs, leaving 65 patients enrolled in the study. 31 (48%) subjects had a CAG < 22, with average age of 67.9 (±12.3). The median duration of hospitalization among subjects with a CAG < 22 was 25 days (95% CI: 9.000–41.6512), and 14 (45.2%) were admitted to the ICU. 34 (52%) subjects had a CAG ≥ 22, their average age was 65.0 (±12.15). Among the 34 subjects with a CAG ≥ 22, the median duration of hospitalization was 47.5 days (95% CI: 22.9533–49.0935), and 24 (70.6%) were admitted to the ICU.

The proportion of subjects admitted to the ICU with CAG < 22 was significantly lower than the proportion of subjects with CAG ≥ 22 (Fisher's exact test P = 0.046791. Subjects with a CAG ≥ 22 had a higher risk for ICU admissions compared to subjects with a CAG < 22: OR: 2.9143(95% CI: 1.0487–8.0985) and likelihood ratio 1.705 (95% CI: 0.985–2.951). Further, estimating 40% of hospitalized COVID‐19 male patients are likely admitted to the ICU, ⁵ the Bayes' adjusted positive predictive value of the AR CAG score in predicting ICU admissions was 53.202% (95% CI: 39.646–66.301) and the negative predictive value was 71.938% (95% CI: 60.693–80.974).

Our data suggest that longer AR CAG score is associated with more severe COVID‐19 disease. In some androgen‐mediated disease, short CAG has been associated with worse prognosis, e.g. in prostate cancer. ⁶ However, in skeletal muscle, a long CAG repeat length produces higher androgen‐mediated activity. ⁷ We believe this discrepancy can be explained by the tissue dependent expression of cofactors important for activation of the androgen response element (ARE). ⁸ For example, protein arginine methyltransferase six has been shown to be highly expressed in lung and has been shown to be a specific co‐activator of the androgen receptor. ⁹

The results of this study suggest that the AR CAG repeat length could potentially be used as a biomarker to identify male COVID‐19 patients at risk for ICU admissions. More importantly, identification of a biomarker associated with the androgen receptor is yet another piece of evidence supporting the important role of androgens in SARS‐CoV‐2 disease severity. We recognize the limitations of this small study; however, our findings, combined with previous reports implicating androgens in COVID‐19 disease severity, ³ , ⁴ , ⁵ should encourage other groups to explore interventional studies of anti‐androgens in COVID‐19‐infected patients. Currently, we are conducting a double‐blinded interventional study with dutasteride (NCT04446429).

Conflicts of interest

None declared.

Funding sources

None.

IRB approval status

The study was approved by the ethics committee at Ramon y Cajal Hospital.

Disclosure

John McCoy, Carlos Gustavo Wambier, Sabina Herrera, Sergio Vaño‐Galván, Francesca Gioia, Belen Comeche, Raquel Ron, Flávio Adsuara Cadegiani, Natasha Atanaskova Mesinkovska, Jerry Shapiro, Rodney Sinclair and Andy Goren have nothing to disclose. Sergio Serrano‐Villar reports grants, personal fees and non‐financial support from Gilead Sciences, grants, personal fees and non‐financial support from Merck, Sharp and Dohme, personal fees and non‐financial support from ViiV Healthcare, personal fees from Janssen, outside the submitted work. Rafal M Iwasiow and Michael A Tayeb reports personal fees from DNA Genotek, Inc. outside the submitted work.