This commentary refers to ‘ACE2 is on the X chromosome: could this explain COVID-19 gender differences?’, by E. Culebras and F. Hernández, 2020:41:3095.
The apparent superiority of women over men in not succumbing to COVID-19 is not completely understood. Therefore, examination of the sex-distinguishing genetics of angiotensin-converting enzyme 2 (ACE2), the host receptor that binds SARS coronaviruses, might help explain this sex disparity.
The ACE2 gene is located on the X chromosome and is expressed in various tissues, including the heart, kidneys, and testes.1 Endogenous soluble ACE2 (found in the circulation) is shed from the cell membrane-bound form and the enzyme responsible for this shedding is ADAM17,2 , 3 which is also membrane anchored. We recently postulated that the co-expression of ACE2 and ADAM17 in the testes (Supplementary figures 5 and 6 in Sama et al. 4) might partially explain why plasma ACE2 concentrations are higher in men than in women.4
We agree with the commentary by Culebras and Hernández5 that the mere occurrence of ACE2 on the X chromosome could also be important in explaining why men would suffer more from ACE2-related diseases than women. In general, based on gene dosage, men suffer more often from X-linked disease traits than do women.6
Future studies relating ACE2 levels to its genomic context, copy number variations, X-inactivation, and various co-morbidities and other (epi)genetic factors are required to improve our understanding of the gender-based disparities in ACE2-related pathophysiology and its relationship to the COVID-19 pandemic.
Funding
This work was supported by a grant from the European Commission (FP7-242209-BIOSTAT-CHF).
Conflict of interest: none declared
Contributor Information
Iziah E Sama, Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Adriaan A Voors, Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
References
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