Abstract
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.
Highlights
SARS-CoV-2 belongs to the β-coronavirus family and the associated severe acute respiratory syndrome (SARS), like the previous SARS-CoV and Middle East respiratory syndrome (MERS-CoV), it may cause life-threatening diseases [1,2,3,4,5,6]
Thrombosis due to coagulation unbalance or inherited or acquired thrombophilia is a rare event among children [13,14,15,16,17], and this could in part account for the micro-thromboembolic events or cardiac injury found in the elderly severest cases as well the rarer disseminated intravascular coagulation (DIC) [18,19,20], strongly substantiating heparin-based anticoagulant treatments in the selected severe cases [18,21,22]
An overly activated renin–angiotensin system (RAS)-system, mainly due to local ACE1/ACE2 unbalancing, might be crucial in determining specific vulnerability/receptivity and in giving indicators of the local balanced inflammation, blood coagulation, and fibrinolysis. These evidences support the use of appropriate anticoagulant and anti-inflammatory therapies properly monitored by specific laboratory markers or with a more refined approach by the dynamic assessing of residual FXIIIA levels, as recently suggested during any acute thrombotic event [182,183]
Summary
SARS-CoV-2 belongs to the β-coronavirus family and the associated severe acute respiratory syndrome (SARS), like the previous SARS-CoV and Middle East respiratory syndrome (MERS-CoV), it may cause life-threatening diseases [1,2,3,4,5,6]. Selected ABO polymorphisms (rs495828, gene promoter, and rs8176746, exon 7) influence ACE inhibitors treatment response [90,91,92], and might contribute in reducing SARS-CoVs’ transmission, in terms of number of infected individuals and epidemic rate reduction This ascribed to O-blood group a lower risk of infection, hypothesizing that natural anti-A and anti-B antibodies can contribute in protecting against viral diseases at the population level [93]. The authors hypothesized that patients characterized by higher ACE1 activity (i.e., D/D-genotype) in conjunction with reduced ACE2 activity (i.e., GG-females or hemizygous G-males) could account for increased susceptibility to hypertension mainly in association with classical cardiovascular risk factors such as old age, dyslipidemia, and diabetes [97] It emerges that an overly activated RAS, exacerbated by genetic predispositions affecting the ACE1/ACE2 balance and in combination with advanced age and classic acquired cardiovascular risk conditions, might lead to systemic disorders and/or severe local disturbances of the normal tissue homeostasis. We have previous experience of dimeric/tetrameric molecules in which selected SNPs seemed to have higher detrimental effects on the molecule structure and activation when combined heterozygous haplotypes were co-inherited in the same carrier rather than in homozygous polymorphic individuals [110,111,112,113,114,115,116]
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