ABSTRACT
Background: COVID-19 outcomes display multiple unexpected varieties, ranging from unnoticed symptomless infection to death, without any previous alarm or known aggravating factors. Aim: To appraise the impact of ACErs4291(A/T) and ERAP1rs26618(T/C) human polymorphisms on the outcome of COVID-19. Subjects and methods: In total, 240 individuals were enrolled in the study (80 with severe manifestations, 80 with mild manifestations, and 80 healthy persons). ACErs4291(A/T) and ERAP1rs26618(T/C) genotyping was performed using RT-PCR. Results: The frequency of the ACErs4291AA genotype was higher among the severe COVID-19 group than others (p < 0.001). The ERAP1rs26618TT genotype frequency was higher among the severe COVID-19 group in comparison with the mild group (p < 0.001) and non-infected controls (p = 0.0006). The frequency of the ACErs4291A allele was higher among severe COVID-19 than mild and non-infected groups (64.4% vs. 37.5%, and 34.4%, respectively), and the ERAP1rs26618T allele was also higher in the severe group (67.5% vs. 39.4%, and 49.4%). There was a statistically significant association between severe COVID-19 and ACErs4291A or ERAP1rs26618T alleles. The coexistence of ACErs4291A and ERAP1rs26618T alleles in the same individual increase the severity of the COVID-19 risk by seven times [OR (95%CI) (LL−UL) = 7.058 (3.752−13.277), p < 0.001). A logistic regression analysis revealed that age, male gender, non-vaccination, ACErs4291A, and ERAP1rs26618T alleles are independent risk factors for severe COVID-19. Conclusions: Persons carrying ACErs4291A and/or ERAP1rs26618T alleles are at higher risk of developing severe COVID-19.
ABSTRACT
The outbreak of coronavirus disease 2019 (COVID-19) was caused by the newly emerged corona virus (2019-nCoV alias SARS-CoV-2) that resembles the severe acute respiratory syndrome virus (SARS-CoV). SARS-CoV-2, which was first identified in Wuhan (China) has spread globally, resulting in a high mortality worldwide reaching ~4 million deaths to date. As of first week of July 2021, ~181 million cases of COVID-19 have been reported. SARS-CoV-2 infection is mediated by the binding of virus spike protein to Angiotensin Converting Enzyme 2 (ACE2). ACE2 is expressed on many human tissues; however, the major entry point is probably pneumocytes, which are responsible for synthesis of alveolar surfactant in lungs. Viral infection of pneumocytes impairs immune responses and leads to, apart from severe hypoxia resulting from gas exchange, diseases with serious complications. During viral infection, gene products (e.g. ACE2) that mediate viral entry, antigen presentation, and cellular immunity are of crucial importance. Human leukocyte antigens (HLA) I and II present antigens to the CD8+ and CD4+ T lymphocytes, which are crucial for immune defence against pathogens including viruses. HLA gene variants affect the recognition and presentation of viral antigenic peptides to T-cells, and cytokine secretion. Additionally, endoplasmic reticulum aminopeptidases (ERAP) trim antigenic precursor peptides to fit into the binding groove of MHC class I molecules. Polymorphisms in ERAP genes leading to aberrations in ERAP's can alter antigen presentation by HLA class I molecules resulting in aberrant T-cell responses, which may affect susceptibility to infection and/or activation of immune response. Polymorphisms from these genes are associated, in global genetic association studies, with various phenotype traits/disorders many of which are related to the pathogenesis and progression of COVID-19; polymorphisms from various genes are annotated in genotype-tissue expression data as regulating the expression of ACE2, HLA's and ERAP's. We review such polymorphisms and illustrate variations in their allele frequencies in global populations. These reported findings highlight the roles of genetic modulators (e.g. genotype changes in ACE2, HLA's and ERAP's leading to aberrations in the expressed gene products or genotype changes at other genes regulating the expression levels of these genes) in the pathogenesis of viral infection.
ABSTRACT
COVID-19 is caused by Severe Acute Respiratory Syndrome Coronavirus-2, which has infected over thirty eight million individuals worldwide. Emerging evidence indicates that COVID-19 patients are at a high risk of developing coagulopathy and thrombosis, conditions that elevate levels of D-dimer. It is believed that homocysteine, an amino acid that plays a crucial role in coagulation, may also contribute to these conditions. At present, multiple genes are implicated in the development of these disorders. For example, single-nucleotide polymorphisms (SNPs) in FGG, FGA, and F5 mediate increases in D-dimer and SNPs in ABO, CBS, CPS1 and MTHFR mediate differences in homocysteine levels, and SNPs in TDAG8 associate with Heparin-induced Thrombocytopenia. In this study, we aimed to uncover the genetic basis of the above conditions by examining genome-wide associations and tissue-specific gene expression to build a molecular network. Based on gene ontology, we annotated various SNPs with five ancestral terms: pulmonary embolism, venous thromboembolism, vascular diseases, cerebrovascular disorders, and stroke. The gene-gene interaction network revealed three clusters that each contained hallmark genes for D-dimer/fibrinogen levels, homocysteine levels, and arterial/venous thromboembolism with F2 and F5 acting as connecting nodes. We propose that genotyping COVID-19 patients for SNPs examined in this study will help identify those at greatest risk of complications linked to thrombosis.