**6. TMPRSS2 polymorphism analysis with COVID-19 disease**

TMPRSS2 and ACE2 have been associated with SARS-corona (CoV) disease, influenza, and SARS-CoV-2 in facilitating viral entrance into the infected host cell TMPRSS2 considers as an androgen-reactive serine protease enzyme that cleaves SARS-CoV-2 Spike protein, mediating viral activation and entry [88]. Singlenucleotide polymorphisms of TMPRSS2 enzyme have been studied in several diseases such as in breast cancer, the rs2276205 (A > G) with low-frequency allele was correlated with increased patients' endurance [89]. In prostate cancer, the rs12329760 (C > T) of TMPRSS2 has a higher frequency in men with prostate cancer in his family, while ERG gene fusion [90, 91] Rs383510 (T > C) and rs2070788

#### **Figure 3.**

*Genetic Variation*

been studied, and it was found that each variant differs in compatibility with RBD sequence. Specifically, although the majority of genetic variants exhibited high physical similarity. Specifically, the two ACE2 gene alleles (rs143936283 and rs73635825) showed a quite low binding strength for the SARS-CoV-2 spike protein, which could mean a lower possibility of viral binding and possible to infection resistance [80]. It has been observed that the probability of some natural genetic variants of ACE2, particularly those assigned to attach with the SARS-CoV-2 spike protein, may be linked with flexible virus-host interaction, thus likely modifying severity and pathogenicity. A large analysis of the genome data-set was performed and showed that no less than nine human ACE2 variants (E23K, S19P, I21V, N64K, K26R, H378R, T27A, T92I, and Q102P) are prospective to increase predisposition to viral binding, while 17 other variants of ACE2 (that is, E37K, K31R, H34R, N33I, E35K, Y50F, D38V, G326E, N51S, M62V, D355N, K68E, F72V, Y83H, D509Y, G352V, and Q388L) were thought to be protected from viral entry, where they demon-

strated a lower binding tendency to SARS-CoV-2 spike protein [81].

In another study, from five separate Italian centers, the authors found that three variants of ACE2 can be specified (p. Gly211Arg, lys26Arg, and p. Asn720Asp). It was noted that these three polymorphisms were recurrently identified in the Italian population rather than the East Asian population. These variants are closely located in the SARS-CoV-2 essential sequence of spike protein binding sites and therefore viral entry and division expected to be modified (for example, Asn720Asp is located

on only 4 amino acids of TMPRSS2 cleavage site) [82]. This may tell a partial explanation for the high case mortality rate registered in Italy by comparison to China. Despite ACE2 practically serve as a receptor for coronavirus SARS entry into human host cells, another does not support the correlation between its common gene polymorphisms and receptivity or consequence of SARS [83]. It has also been observed that some ACE2 variants show differential efficacy in stimulating neutrophils, monocytes, natural killer cells (NK), macrophages, and T helper cells, thus

*Diagrammatic representation for the renin-angiotensin system (RAS) pathway. As ACE2/Ang 1-7/ Mas-axis and ACE1/Ang-II/ AT1R-axis occur, SARS-CoV-2 inhibition by cleavage of ACE2 by ADAM17 appears. ADAM17: ADAM metallopeptidase domain 17; ARBs: angiotensin receptor blockers; MRAs:* 

**182**

**Figure 2.**

*mineralocorticoid receptor antagonists [87].*

*A polymorphism and dysregulation of ACE2, and TMPRSS2 in COVID-19 and a suggested model for active compound medicines (e.g., hydroxychloroquine, Camostat mesylate, and E-64D [a protease inhibitor] for COVID-19) [93].*

(G > A) were correlated with aggressive H7N9, H1N1, and increased lung expression of TMPRSS2 [92]. A study by Hou et al., indicated that 4% of nonidentical variants of TMPRSS2 are stop-codon mutations, Meanwhile, 59% are harmful mutations in TMPRSS2 coding regions [93]. The harmful variants (p.Arg240Cys, p.Val160Met, p.Gly181Arg, p.Pro335Leu, p.Gly432Ala, and p.Gly259Ser) in the coding region of TMPRSS2, are the same with somatic alterations arising in various types of cancer. In the same contest, Hou et al. found that, the p. Asp435Tyr which is a key site for catalytic residue binding of TMPRSS2 has unique low-frequency allele, but predominant SNPs in TMPRSS2 and offer possible descriptions for differential genetic infectivity to COVID-19 and for risk influences, such as those with tumor and male patients. By using the analysis of single-cell RNA-seq, Schuler et al. revealed that the expression of TMPRSS2 was upregulated in ciliated cells and alveolar epithelial type 1 cells and increased with humans aging [94]. This observation indicates that the developmental TMPRSS2 expression regulation may have a role in the relative protection of the children and infants from COVID-19 infection. Yet, it might be of great importance to investigate the link between TMPRSS2 polymorphisms and the age relationship with COVID-19 susceptibility (**Figure 3**).
