**3. ACE2 expression in human tissues**

The expression of ACE2 in the different human tissues was controversial because ACE2 was newly identified as a major binding site across which SARS-CoV-2 enters human host cells. Recently, many studies were performed to detect the cell types where ACE2 receptor is mainly expressed, which could describe the possible SARS-CoV-2 targets. One study was conducted to address the expression of ACE2 in various natural human tissues, and the analysis of the results regarding age and sex. Highest ACE2 expression levels were detected in the tissues of the small intestine, testicle, thyroid heart, adipose tissues, and kidneys. Esophagus, pancreas, lungs, liver, adrenal gland bladder, and colon were found to express the intermediate level while the lowest expression was found in the stomach nerves, blood vessels, uterus, muscle, spleen, bone marrow, and brain. Regarding lungs, the levels of ACE2 expression were upregulated and downregulated in relation to the immune pattern of men and women respectively [49]. ACE2 also was expressed in certain types of epithelial cells in the airway, such as type II alveolar epithelial cells and ciliated nasal epithelium. Moreover, it was found to be highly co-expressed with the TMPRSS2 in the nasal epithelium, which explains their higher infectivity by COVID-19 [50]. ACE2 is localizing also on the oral cavity mucosa. For now, these results revealed the underlying mechanism that the oral cavity poses a significant potential risk for 2019-nCoV susceptibility, and ACE2 was also expressed in lymphocytes inside the oral mucosa [51]. These findings have reminded us that COVID-19 attacks the lymphocytes and causes lymphopenia, mostly in severe forms of the disease [52].

More importantly, ACE2 also are expressed in endothelial cells [53]. That explains why COVID-19 disease affects multiorgan in the patients [54]. these results indicate that SARS-CoV-2 virus promotes the initiation of endotheliitis in many organs as a direct result of the viral intervention and the inflammatory response of the host. Additionally, the triggering of pyroptosis and apoptosis may have an important role in endothelial cell injury in COVID-19 patients and can account for the weakened systemic microcirculatory performance in various blood vessels and their clinical consequences in COVID-19 patients [55]. This supposition affords justifications for treatments to stabilize the endothelium during viral reproduction, especially by anti-inflammatory cytokines drugs, cholesterol-lowering drugs, and ACE inhibitors [56–59]. This approach can be especially appropriate for weak patients with an earlier endothelial disorder, such as hypertension, diabetes mellitus, obesity, cardiovascular disease co-morbidities patients [55].

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*Co-Evolution between New Coronavirus (SARS-CoV-2) and Genetic Diversity…*

polymorphism has been described in African- Americans with HT [74].

**5. Viral ACE2 receptor polymorphism and coronavirus infection**

ACE2 gene variants are still possible to affect SARS-CoV-2 infectivity. In SARS-CoV, the function of the S1 domain of the S protein is to mediate the binding of ACE2 receptors while the S2 domain is potentially undergoing post binding transconformational modulations which activate the fusion to the cell membrane [75]. The viral (RBD) found in S1 has been adjusted to amino acid number 270 to 510 [76]. The Leu584Ala point mutation of ACE2 significantly weakened the shedding activity of the enzyme and promoted the entrance of SARS-CoV into the host cells [77]. An ACE2 soluble form lacks the transmembrane and cytoplasmic domain was stated able to prevent SARS-CoV S protein binding to ACE2 [46]. Recombinant SARS-CoV-2 spike proteins were observed to downregulated ACE2 expression by releasing sACE2 and thus enhancing injury of the lung [78]. SARS-CoV and SARSCoV-2 participate in the identity of 76% of the amino acid residues necessary for binding of ACE2 within the SARS-CoV-2 spike S1 domain. A lot of amino acid residues of the ten human ACE2 proteins were compared by multiple sequence alignment, a 100% identity among the ACE2 sequences was observed in four different ACE2 isoforms. The role of these ACE2 isoforms remains unpredictable in SARS-CoV-2 infection outcome. According to the work by Cao et al., [61] 32 polymorphisms of ACE2, including 7 hotspot variables (Ile486Val, Lys26Arg, Asn638Ser, Asn720Asp, Ser692Pro, Ala627Val, and Leu731Ile/Phe) were identified in different peoples, that make some individuals could be more or less susceptible to the virus than others.

In a preliminary study, the distribution of the allele frequency for 1700 polymorphisms in the ACE2 gene was conducted between various populations of the world. What is noteworthy is that 11 common and rare variants were detected linked to the high ACE2 expression. It was observed that their expression is irregularly distributed among different populations groups. This study found that the polymorphism of the ACE2 gene (variant 4,646,127) was closely related to the higher expression levels of the ACE2 gene in the East Asian population, and this paved the way to study this important issue more specifically [61]. These results were confirmed by a similar subsequent study by [79], which also evidenced that the allele frequency of these variants associated with overexpression of ACE2. Also, different ACE2 polymorphisms encoded a number of proteins for SARS-CoV-2 spike protein has

**4. Implication of human polymorphism of ACE2 in disease susceptibility**

A lot of ACE2 variants have been recognized in different databases [60, 61]. over the last decades, much focus has been assigned on some of ACE2 polymorphisms, due to their effects on the development of cardiovascular disease (CVD) and, more specifically, their association with hypertension (HT). ACE2 restricts the negative profibrotic and vasoconstrictor influences of AngII, as the breakdown of AngII to Ang (1-7) decreases the AngII oxidative stress of the cerebral arteries endothelium [62]. Ang (1-7) has been stated to have antifibrotic and vasodilation [63, 64]. Low cardiac expression of ACE2 levels has been notified in hypertension and diabetes heart failure [65, 66]. ACE2 gene polymorphisms were first detected in the Chinese people with different ACE2 variants (rs4830542, rs4240157, and rs4646155) linked to hypertension (HT) [67–70]. Also, ACE2 SNP rs21068809 (C > T) was found to be linked to the clinical features of HT [71]. In India, a study of 246 patients with HT and 274 normal subjects showed a connection of ACE2 rs21068809 SNP with HT [72]. in Brazilian cohorts, a study of genetic association of the combination of ACE2 G8790A and ACE I/D polymorphisms reveal susceptibility to HT [73]. ACE

*DOI: http://dx.doi.org/10.5772/intechopen.93676*
