SNPs can be synonymous or silent (i.e., do not cause a change in amino acid), and non-synonymous (when an amino acid changes). Synchronous SNPs have been thought to be insignificant, because the original protein sequence is preserved. Several studies have challenged this hypothesis over the past decade and shown that, synonymous mutations can also be contributed to disease. A lot of evidence shows that, synonymous SNPs can actually disrupt cellular function and create distinct clinical phenotypes. Synonymous SNPs, often can alter transcriptional stability by changing the ability of RNA-bound proteins to detect transcription through changes in mRNA structure. The secondary structure of mRNA is important in the synthesis and processing of pre-mRNA, as well as translation control. Thus, synonymous SNP, which that alters mRNA structure, can affect numerous cellular functions. Also, some synonymous mutations can turn off the effects of a harmful mutation (Higgs and Ran, 2008, Hunt et al., 2009). A1AT protein contains 394 amino acids consisting of 3 β-sheets, 9 α-helices, and a reactive center loop (Dafforn et al., 2004). Point mutations can destabilize the A β-sheet, and destroy the structure of the protein, and finally, by protein-protein interaction, and binding the residues of one serpin molecule to the β-sheet of another molecule, forms a loop-sheet polymer. These polymers accumulate within the endoplasmic reticulum of liver cells and create the inclusion bodies, which leading to several diseases such as liver cirrhosis, liver carcinoma, emphysema, and thrombosis (Green et al., 2003, James and Bottomley, 1998, Peltier et al., 2000). Milger et al., reported that a 44-year-old non-smoking woman of Turkish origin, who had suffered severe dyspnea and inspiratory pulmonary pain, a chest computed tomography scan confirmed severe bronchiectasis, severe emphysema, and pulmonary embolism. Pulmonary function tests showed severe obstruction and moderate swelling. In the patient's biochemical investigations, leukocytosis, elevated C-reactive protein, thrombocytosis, eosinophilia, respiratory failure, and low serum A1AT levels (25 mg /dl), were identified. Genotypic screening did not show any S and Z mutations in exons III and V of the SERPINA1 gene. However, after sequencing the remaining exons of the SERPINA1 gene, the insertion of a homozygous CA dinucleotide into exon II was found, which leading to a frameshift mutation in the stop codon at locus 219 (Milger et al., 2015).
Studies have also shown that A1AT directly inhibits the activity of caspase-3, an intracellular cysteine protease that plays a key role in cellular apoptosis (Petrache et al., 2006). Activation of Caspase-3 at the death time of neutrophils is well documented, recent findings provide evidence that, cut and activation of procaspsase-3 are due to the release of PR3 (protease 3) from neutrophil granules into the cytosol. Activation of caspase-3 by PR3 plays an important role in neutrophil apoptosis (Luo and Loison, 2008).
A1AT is involved in the inhibition of gelatinase B (MMP-9) in neutrophils. Neutrophils have been identified as the predominant source of MMP-9 (Gettins, 2002). MMP-9 is formed during the maturation of neutrophils, and helps neutrophil depletion and stem cell mobilization by destroying basement membrane collagens (Bradley et al., 2012). A1AT is an indirect physiological inhibitor of MMP-9, because elastase inactivates the MMP-9 activator (Opdenakker et al., 1998). Previous studies have also shown that, A1AT genetic defect can affect neutrophil elastase activity, as well as lung tissue organization, through the enzyme lysyl oxidase, which is responsible for cross-linking between tropoelastin molecules (Crystal, 1990, Janoff, 1985).
The starting ATG sequence for the 24th amino acid’s peptide signal as well as, 2 of the 3 sites of glycosylation of the SERPINA1 gene is located in exon II. Exon III has the third glycosylation site (Crystal et al., 1989, Crystal, 1989). A1AT has a variety of anti-inflammatory properties; it has been shown that, A1AT can modulate the resulting chemotaxis by binding to IL8. At physiological pH, the A1AT protein has an overall negative charge that causes an electrostatic interaction between A1AT and IL-8 with a positive charge.
A1AT oligosaccharides are critical for this anti-inflammatory function, because it has been shown that, A1AT cannot bind to IL8 without glycosylation. Binding between A1AT and IL-8 inhibits IL-8 binding to CXCR1, which negatively affects downstream signaling events in cytoskeletal rearrangement, F-actin formation, and calcium charging, and ultimately reduces neutrophil migration (Ferry et al., 1997). Significantly, disorders of inflammatory regulation and blood coagulation have been reported to be involved in varying intensities of COVID-19 (Bergin et al., 2010).
The SERPINA1 gene is part of a group of genes that include cortisol-binding globulin, alpha 1 antichymotrypsin, a protease-like inhibitor, and a protein C inhibitor, all of which are located near the locus of immunoglobulin’s, the link between the locus of immunoglobulin’s, and the locus of protease inhibitors may be the cause of SERPINA1 deficiency diseases and several inflammatory diseases(Crystal, 1989, Dafforn et al., 1999). According to our results we supposed that, due to changes of synonymous and non-synonymous polymorphisms in the structure and function of A1AT, in the entry and infection by SARS-COV2, the coagulation pathway, protease/antiprotease balance and inflammation, the severity of COVID- 19 can be changed in 3 outpatient, inpatient and ICU groups, as imagined among the non-synonymous SNPs, the 5895 C > G locus polymorphism with a frequency of 33.3% (exons 2, 14 of 42 total samples) that observed only in the ICU group, compared with the two synonymous polymorphisms at the 5646 and 5892 loci (exons 2) Causes high sensitivity to SARS-COV-2. Also, among the synonymous polymorphisms of SNP, position 11295 with a frequency of 21.4% (exons 5, 9 of 42 total samples) in the outpatient group, probably; has shown the highest resistance against COVID-19.