key: cord-0684183-cohnyjp2 authors: Sama, Iziah E; Voors, Adriaan A title: Men more vulnerable to COVID-19: explained by ACE2 on the X chromosome? date: 2020-06-24 journal: Eur Heart J DOI: 10.1093/eurheartj/ehaa526 sha: 1413373c5d6bce1397c64548e3eca8f23f93a745 doc_id: 684183 cord_uid: cohnyjp2 nan 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 Hernández 5 that the mere occurrence of ACE2 on the X chromosome could also be important in explaining why men would suffer more from ACE2related 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. This work was supported by a grant from the European Commission (FP7-242209-BIOSTAT-CHF). A novel angiotensinconverting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9 Tumor necrosis factor-alpha convertase (ADAM17) mediates regulated ectodomain shedding of the severe-acute respiratory syndrome-coronavirus (SARS-CoV) receptor, angiotensin-converting enzyme-2 (ACE2) Selective and specific regulation of ectodomain shedding of angiotensin-converting enzyme 2 by tumor necrosis factor alpha-converting enzyme Circulating plasma concentrations of angiotensin-converting enzyme 2 in men and women with heart failure and effects of renin-angiotensin-aldosterone inhibitors ACE2 is on the X chromosome: could this explain COVID-19 gender differences? X-linked diseases: susceptible females ), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use DISCUSSION FORUM