Influence of IL-6 rs1800795 and IL-8 rs2227306 polymorphisms on COVID-19 outcome.

INTRODUCTION: Severe coronavirus disease 2019 (COVID-19) is mainly precipitated by an uncontrolled inflammatory response and cytokine storm. Pro-inflammatory cytokines such as IL-6 and IL-8 levels were markedly increased in complicated cases. Genetic polymorphisms may have a role in this dysregulated expression during SARS-CoV-2 infection. Our aim was to assess the influence of IL-6 and IL-8 single nucleotide polymorphisms (SNPs) on COVID-19 outcomes. METHODOLOGY: 240 subjects were involved in the study; 80 cases with severe COVID-19, 80 cases with mild COVID-19, and 80 healthy subjects. IL-6rs1800795(G/C) and IL-8 rs2227306(C/T) genotyping was performed using real-time polymerase chain reaction (PCR). RESULTS: Ages ranged between 20-67 years in all groups. There was a statistically significant association between the male gender and severe COVID-19. A significantly higher expression of IL-6rs1800795GG and IL-8rs2227306CC genotypes was observed among patients with severe COVID-19 than other groups. At the allele level, IL-6rs1800795G and IL-8rs2227306C alleles were more frequent among patients with severe COVID-19 when compared with other groups. Haplotypes' frequency clarified that the coexistence of IL-6 rs1800795G and IL-8rs2227306C alleles in the same person increased the risk of severe COVID-19 outcomes. Carriers of IL-6rs1800795C and IL-8 rs2227306T alleles are at lower risk of developing severe COVID-19. Multivariate logistic regression analysis showed that old age, male gender, IL-6 rs1800795CG+GG, and IL-8 rs2227306CT+CC genotypes could be independent risk factors for severe COVID-19 outcomes. CONCLUSIONS: IL-6 rs1800795G and IL-8 rs2227306C alleles are significantly associated with severe COVID-19 outcomes, especially if they coexist. They may be used as prognostic markers for COVID-19.

Relevance of HLA-DP/DQ and INF-λ4 Polymorphisms to COVID-19 Outcomes

Background: Single nucleotide polymorphisms provide information on individuals' potential reactions to environmental factors, infections, diseases, as well as various therapies. A study on SNPs that influence SARS-CoV-2 susceptibility and severity may provide a predictive tool for COVID-19 outcomes and improve the customized coronavirus treatment. Aim: To evaluate the role of human leukocyte antigens DP/DQ and IFNλ4 polymorphisms on COVID-19 outcomes among Egyptian patients. Participants and Methods: The study involved 80 patients with severe COVID-19, 80 patients with mild COVID-19, and 80 non-infected healthy volunteers. Genotyping and allelic discrimination of HLA-DPrs3077 (G/A), HLA-DQrs7453920 (A/G), and IFNλ4 rs73555604 (C/T) SNPs were performed using real-time PCR. Results: Ages were 47.9 ± 8, 44.1 ± 12.1, and 45.8 ± 10 years in severe, mild and non-infected persons. There was a statistically significant association between severe COVID-19 and male gender (p = 0.002). A statistically significant increase in the frequency of HLA-DPrs3077G, HLA-DQrs7453920A, and IFNλ4rs73555604C alleles among severe COVID-19 patients when compared with other groups (p < 0.001). Coexistence of these alleles in the same individual increases the susceptibility to severe COVID-19 by many folds (p < 0.001). Univariate and multivariate logistic regression analysis for the studied parameters showed that old age, male gender, non-vaccination, HLA-DQ rs7453920AG+AA, HLA-DPrs3077GA+GG, and IFNλ4rs73555604CT+CC genotypes are independent risk factors for severe COVID-19 among Egyptian patients. Conclusion: HLA-DQ rs7453920A, HLA-DPrs3077G, and IFNλ4rs73555604C alleles could be used as markers of COVID-19 severity.

Relevance of HLA-DP/DQ and INF-λ4 Polymorphisms to COVID-19 Outcomes.

Background: Single nucleotide polymorphisms provide information on individuals' potential reactions to environmental factors, infections, diseases, as well as various therapies. A study on SNPs that influence SARS-CoV-2 susceptibility and severity may provide a predictive tool for COVID-19 outcomes and improve the customized coronavirus treatment. Aim: To evaluate the role of human leukocyte antigens DP/DQ and IFNλ4 polymorphisms on COVID-19 outcomes among Egyptian patients. Participants and Methods: The study involved 80 patients with severe COVID-19, 80 patients with mild COVID-19, and 80 non-infected healthy volunteers. Genotyping and allelic discrimination of HLA-DPrs3077 (G/A), HLA-DQrs7453920 (A/G), and IFNλ4 rs73555604 (C/T) SNPs were performed using real-time PCR. Results: Ages were 47.9 ± 8, 44.1 ± 12.1, and 45.8 ± 10 years in severe, mild and non-infected persons. There was a statistically significant association between severe COVID-19 and male gender (p = 0.002). A statistically significant increase in the frequency of HLA-DPrs3077G, HLA-DQrs7453920A, and IFNλ4rs73555604C alleles among severe COVID-19 patients when compared with other groups (p < 0.001). Coexistence of these alleles in the same individual increases the susceptibility to severe COVID-19 by many folds (p < 0.001). Univariate and multivariate logistic regression analysis for the studied parameters showed that old age, male gender, non-vaccination, HLA-DQ rs7453920AG+AA, HLA-DPrs3077GA+GG, and IFNλ4rs73555604CT+CC genotypes are independent risk factors for severe COVID-19 among Egyptian patients. Conclusion: HLA-DQ rs7453920A, HLA-DPrs3077G, and IFNλ4rs73555604C alleles could be used as markers of COVID-19 severity.

Impact of ACE and Endoplasmic Reticulum Aminopeptidases Polymorphisms on COVID-19 Outcome.

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.

The Pre-Vaccination Donated Blood Is Free from Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) but Is Rich with Anti-SARS-CoV-2 Antibodies: A Cross-Section Saudi Study.

(1) Backgrounds and Objectives: Since its discovery, information about the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) has spread rapidly. However, many issues remain unresolved. Coronaviruses are primarily transmitted through respiratory secretions. The possibility of transmission via donated blood transfusion deserves studying. This is the first study in Saudi Arabia to look at pre-vaccination donated blood anti-SARS-CoV-2 antibody content as a marker for virus transmission via viral RNA positive blood and/or the potential therapeutic value of convalescent plasma. (2) Methods: A total of 300 blood samples were sequentially collected from unvaccinated donors who donated blood to the blood bank of Prince Mutaib Bin Abdulaziz Hospital in Sakaka, Al-Jouf, Saudi Arabia. Specific ELISA was used to detect anti-SARS-CoV-2 IgG and IgM antibodies. SARS-CoV-2 was detected using specific real-time reverse-transcription PCR (rRT-PCR). (3) Results: The prevalence of anti-SARS-CoV-2 IgG was low (9%), whereas the prevalence of anti-SARS-CoV-2 IgM was high (65%). Relevant demographics, anthropometrics, and lifestyle factors revealed significant associations (p < 0.05) between IgM-positivity only vs. age (age group 21-30 years), postgraduate education, no history of international travel, IgG-negativity, and absence of experience with COVID-19-like symptoms. Furthermore, there are significant associations (p < 0.05) between IgG-positivity only vs. age (age group 21-30 years), postgraduate education, and being a non-healthcare worker. All donors in the anti-SARS-CoV-2 IgG-positive group (n = 27) had previously experienced symptoms similar to COVID-19 (p < 0.001) and most of them (n = 24) showed anti-SARS-CoV-2 IgM-positive test (p = 0.006). However, all the samples tested negative for SARS-CoV-2 RNA using rRT-PCR. (4) Conclusion: Our findings add to the growing body of evidence that donated blood is safe, with the added benefit of convalescent plasma rich in potentially neutralizing IgG and IgM against SARS-CoV-2.

Relevance between COVID-19 and host genetics of immune response.

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.

Prognostic Genetic Markers for Thrombosis in COVID-19 Patients: A Focused Analysis on D-Dimer, Homocysteine and Thromboembolism.

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.