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COVID-19 and Individual Genetic Susceptibility/Receptivity: Role of ACE1/ACE2 Genes, Immunity, Inflammation and Coagulation. Might the Double X-Chromosome in Females Be Protective against SARS-CoV-2 Compared to the Single X-Chromosome in Males?

1
Department of Morphology, Surgery and Experimental Medicine and Centre Haemostasis & Thrombosis, University of Ferrara, 44121 Ferrara, Italy
2
University Centre for Studies on Gender Medicine, University of Ferrara, 44121 Ferrara, Italy
3
Department of Biomedical & Specialty Surgical Sciences, University of Ferrara, 44121 Ferrara, Italy
4
Department of Medical Sciences and Centre Haemostasis & Thrombosis, University of Ferrara, 44121 Ferrara, Italy
5
Department of Morphology, Surgery and Experimental Medicine and LTTA Centre, University of Ferrara, 44121 Ferrara, Italy
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2020, 21(10), 3474; https://doi.org/10.3390/ijms21103474
Received: 15 April 2020 / Revised: 9 May 2020 / Accepted: 11 May 2020 / Published: 14 May 2020
(This article belongs to the Special Issue Gender Medicine: Pharmacogenetics and Personalised Medicine)
In December 2019, a novel severe acute respiratory syndrome (SARS) from a new coronavirus (SARS-CoV-2) was recognized in the city of Wuhan, China. Rapidly, it became an epidemic in China and has now spread throughout the world reaching pandemic proportions. High mortality rates characterize SARS-CoV-2 disease (COVID-19), which mainly affects the elderly, causing unrestrained cytokines-storm and subsequent pulmonary shutdown, also suspected micro thromboembolism events. At the present time, no specific and dedicated treatments, nor approved vaccines, are available, though very promising data come from the use of anti-inflammatory, anti-malaria, and anti-coagulant drugs. In addition, it seems that males are more susceptible to SARS-CoV-2 than females, with males 65% more likely to die from the infection than females. Data from the World Health Organization (WHO) and Chinese scientists show that of all cases about 1.7% of women who contract the virus will die compared with 2.8% of men, and data from Hong Kong hospitals state that 32% of male and 15% of female COVID-19 patients required intensive care or died. On the other hand, the long-term fallout of coronavirus may be worse for women than for men due to social and psychosocial reasons. Regardless of sex- or gender-biased data obtained from WHO and those gathered from sometimes controversial scientific journals, some central points should be considered. Firstly, SARS-CoV-2 has a strong interaction with the human ACE2 receptor, which plays an essential role in cell entry together with transmembrane serine protease 2 (TMPRSS2); it is interesting to note that the ACE2 gene lays on the X-chromosome, thus allowing females to be potentially heterozygous and differently assorted compared to men who are definitely hemizygous. Secondly, the higher ACE2 expression rate in females, though controversial, might ascribe them the worst prognosis, in contrast with worldwide epidemiological data. Finally, several genes involved in inflammation are located on the X-chromosome, which also contains high number of immune-related genes responsible for innate and adaptive immune responses to infection. Other genes, out from the RAS-pathway, might directly or indirectly impact on the ACE1/ACE2 balance by influencing its main actors (e.g., ABO locus, SRY, SOX3, ADAM17). Unexpectedly, the higher levels of ACE2 or ACE1/ACE2 rebalancing might improve the outcome of COVID-19 in both sexes by reducing inflammation, thrombosis, and death. Moreover, X-heterozygous females might also activate a mosaic advantage and show more pronounced sex-related differences resulting in a sex dimorphism, further favoring them in counteracting the progression of the SARS-CoV-2 infection. View Full-Text
Keywords: SARS-CoV-2; COVID-19; ACE1; ACE2; RAS-pathway; TMPRSS2; sex/gender-gap; lung shut-down; prognostic molecular/genetic markers; inflammation; thrombosis SARS-CoV-2; COVID-19; ACE1; ACE2; RAS-pathway; TMPRSS2; sex/gender-gap; lung shut-down; prognostic molecular/genetic markers; inflammation; thrombosis
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MDPI and ACS Style

Gemmati, D.; Bramanti, B.; Serino, M.L.; Secchiero, P.; Zauli, G.; Tisato, V. COVID-19 and Individual Genetic Susceptibility/Receptivity: Role of ACE1/ACE2 Genes, Immunity, Inflammation and Coagulation. Might the Double X-Chromosome in Females Be Protective against SARS-CoV-2 Compared to the Single X-Chromosome in Males? Int. J. Mol. Sci. 2020, 21, 3474. https://doi.org/10.3390/ijms21103474

AMA Style

Gemmati D, Bramanti B, Serino ML, Secchiero P, Zauli G, Tisato V. COVID-19 and Individual Genetic Susceptibility/Receptivity: Role of ACE1/ACE2 Genes, Immunity, Inflammation and Coagulation. Might the Double X-Chromosome in Females Be Protective against SARS-CoV-2 Compared to the Single X-Chromosome in Males? International Journal of Molecular Sciences. 2020; 21(10):3474. https://doi.org/10.3390/ijms21103474

Chicago/Turabian Style

Gemmati, Donato, Barbara Bramanti, Maria L. Serino, Paola Secchiero, Giorgio Zauli, and Veronica Tisato. 2020. "COVID-19 and Individual Genetic Susceptibility/Receptivity: Role of ACE1/ACE2 Genes, Immunity, Inflammation and Coagulation. Might the Double X-Chromosome in Females Be Protective against SARS-CoV-2 Compared to the Single X-Chromosome in Males?" International Journal of Molecular Sciences 21, no. 10: 3474. https://doi.org/10.3390/ijms21103474

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