An Updated Review on the Role of Single Nucleotide Polymorphisms in COVID-19 Disease Severity: A Global Aspect

Coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and recently has become a serious global pandemic. Age, gender, and comorbidities are known to be common risk factors for severe COVID-19 but are not enough to fully explain the magnitude of their effect on the risk of severity of the disease. Single nucleotide polymorphisms (SNPs) in several genes have been reported as a genetic factor contributing to COVID-19 severity. This comprehensive review focuses on the association between SNPs in four important genes and COVID-19 severity in a global aspect. We discuss a total of 39 SNPs in this review: five SNPs in the ABO gene, nine SNPs in the angiotensin-converting enzyme 2 (ACE2) gene, 19 SNPs in the transmembrane protease serine 2 (TMPRSS2) gene, and six SNPs in the toll-like receptor 7 (TLR7) gene. These SNPs data could assist in monitoring an individual's risk of severe COVID-19 disease, and therefore personalized management and pharmaceutical treatment could be planned in COVID-19 patients.

Bioinformatic Evaluation of the miRNAs Targeting ACE2 Gene in COVID-19

Introduction: Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), which began in late 2019 in Wuhan, China, has become a global epidemic. Angiotensin 2 converting enzyme (ACE2) acts as a receptor for host function to cause acute coronavirus 2 acute respiratory syndrome (SARS-CoV-2). ACE2 is abundantly expressed in different cells of different human organs. In human physiology, ACE2 is a major player in the renin-angiotensin-aldosterone (RAAS) system by degrading angiotensin II. Many factors have been associated with altered ACE2 expression and the severity and progression of COVID-19, including microRNAs that may be effective in it. Identifying pathological changes due to SARS-CoV-2 infection is important because it has major implications for understanding the pathophysiology of COVID-19 and developing evidence-based treatment strategies. Currently, many intervention strategies are being explored in ongoing clinical trials. Objective: The aim of this study is to use bioinformatics databases to find potential antiviral therapies against SARS-CoV-2 through host microRNAs (miRNAs) that can reduce viral gene expression to inhibit virus entry and replication. Methods: Using different algorithms in TargetScan, DIANA, ENCORI and miRWalk databases, the potential microRNAs were identified that target ACE2. Then, a score table was prepared from the candidate microRNAs, based on the affinity of the seed region of microRNAs and the 3`-UTR region of the ACE2 gene. Finally, microRNAs with higher scores were chosen as candidates for practical analysis. Results: The results of Bioinformatical analysis showed that Has-miR-200c-3p, Has-miR-29a, Has-miR-29c, and Has-miR-942 are most likely to inhibit ACE2. These microRNAs are the most potent factors that might be affected on ACE2 during virulence. Conclusion: It seems that ACE2 is under the control of the miR-200c-3p and plays a crucial role in the pathophysiology process. Therefore, this microRNA can be considered as a suitable new candidate for experimental evaluation.

The Susceptibility of Healthy People to COVID-19 Infection and the Role of ACE2

The COVID-19 virus has caused many deaths of people worldwide since the pandemic began. However, no definitive treatment for this infection has been discovered so far. It has been shown that comorbidities such as diabetes, hypertension and cardiovascular diseases are associated with an increased risk of SARS-COV-2 infection. Interestingly, SARS-COV-2, like SARS-COV, uses the ACE2 gene to enter the host cell. Also, changes or imbalance in ACE2.ACE can affect SARS-COV-2 susceptibility, related outcomes and mortality. Regarding the crucial role of ACE2 protein in COVID-19 infection, the effect of different factors such as age, BMI, physical activity levels, nutritional status, altitude, as well as blood group was assessed on the level of this protein. Further, to our knowledge, no study has been conducted to examine factors that increase or decrease the risk of COVID-19 and its related severity and outcome in normal subjects emphasizing the pivotal role of ACE2. Therefore, the primary purpose of this study was to investigate the involved mechanisms of ACE2 protein and other risk factors causing infection in different situations and finally, to introduce a safe, accurate, and cost-effective approach to prevent SARS-COV-2 infection and hard clinical outcomes in normal subjects.

SARS-CoV-2 Infection Modulates ACE2 Function and Subsequent Inflammatory Responses in Swabs and Plasma of COVID-19 Patients

Angiotensin converting enzyme 2 (ACE2) is a host ectopeptidase and the receptor for the SARS-CoV-2 virus, albeit virus-ACE2 interaction goes far beyond viral entry into target cells. Controversial data exists linking viral infection to changes in ACE2 expression and function, which might influence the subsequent induction of an inflammatory response. Here, we tested the significance of soluble ACE2 enzymatic activity longitudinally in nasopharyngeal swabs and plasma samples of SARS-COV-2 infected patients, along with the induction of inflammatory cytokines. Release of soluble functional ACE2 increases upon SARS-CoV-2 infection in swabs and plasma of infected patients, albeit rapidly decreasing during infection course in parallel with ACE2 gene expression. Similarly, SARS-CoV-2 infection also induced the expression of inflammatory cytokines. These changes positively correlated with the viral load. Overall, our results demonstrate the existence of mechanisms by which SARS-CoV-2 modulates ACE2 expression and function, intracellular viral sensing and subsequent inflammatory response, offering new insights into ACE2 dynamics in the human upper respiratory tract and pointing towards soluble ACE2 levels as a putative early biomarker of infection severity.

ACE2 Netlas: In silico Functional Characterization and Drug-Gene Interactions of ACE2 Gene Network to Understand Its Potential Involvement in COVID-19 Susceptibility

Angiotensin-converting enzyme-2 (ACE2) receptor has been identified as the key adhesion molecule for the transmission of the SARS-CoV-2. However, there is no evidence that human genetic variation in ACE2 is singularly responsible for COVID-19 susceptibility. Therefore, we performed an integrative multi-level characterization of genes that interact with ACE2 (ACE2-gene network) for their statistically enriched biological properties in the context of COVID-19. The phenome-wide association of 51 genes including ACE2 with 4,756 traits categorized into 26 phenotype categories, showed enrichment of immunological, respiratory, environmental, skeletal, dermatological, and metabolic domains (p < 4e-4). Transcriptomic regulation of ACE2-gene network was enriched for tissue-specificity in kidney, small intestine, and colon (p < 4.7e-4). Leveraging the drug-gene interaction database we identified 47 drugs, including dexamethasone and spironolactone, among others. Considering genetic variants within ± 10 kb of ACE2-network genes we identified miRNAs whose binding sites may be altered as a consequence of genetic variation. The identified miRNAs revealed statistical over-representation of inflammation, aging, diabetes, and heart conditions. The genetic variant associations in RORA, SLC12A6, and SLC6A19 genes were observed in genome-wide association study (GWAS) of COVID-19 susceptibility. We also report the GWAS-identified variant in 3p21.31 locus, serves as trans-QTL for RORA and RORC genes. Overall, functional characterization of ACE2-gene network highlights several potential mechanisms in COVID-19 susceptibility. The data can also be accessed at https://gpwhiz.github.io/ACE2Netlas/.

SARS-CoV-2 susceptibility and ACE2 gene variations within diverse ethnic backgrounds

Background Host genetics play a major role in COVID-19 susceptibility and severity. Here, we analyse an ethnically diverse cohort of National Health Service (NHS) patients in the United Kingdom (UK) to assess the association between variants in the ACE2 locus and COVID-19 risk. Methods We analysed whole-genome sequencing (WGS) data of 6,274 participants who were tested for SARS-CoV-2 from the UK's 100,000 Genomes Project (100KGP) for the presence of ACE2 variants and expression quantitative trait loci (eQTLs). Findings We identified a splice site variant (rs2285666) associated with increased ACE2 expression with an overrepresentation in SARS-CoV-2 positive patients relative to 100KGP controls (p = .015), and in hospitalised European patients relative to outpatients in intra-ethnic comparisons (p = .029). We also compared the prevalence of 288 eQTLs, of which 23 were enriched in SARS-CoV-2 positive patients. The eQTL rs12006793 had the largest effect size (d = 0.91), which decreases ACE2 expression and is more prevalent in controls, thus potentially reducing risk of COVID-19. We identified three novel nonsynonymous variants predicted to alter ACE2 function, and showed that three variants (p.K26R, p.H378R, p.Y515N) alter receptor affinity for the viral Spike (S) protein. Variants p.K26R and p.N720D are more prevalent in the European population (p < .001), but Y497H is less prevalent compared to East Asians (p = .020). Interpretation Our results demonstrate that the spectrum of genetic variants in ACE2 may inform risk stratification of COVID-19 patients and could partially explain the differences in disease susceptibility and severity among different ethnic groups. Funding The 100KGP is funded by the National Institute for Health Research and NHS England. Funding was also obtained from Stanford University, Palo Alto.

Angiotensin-Converting Enzyme 2 (ACE2) in the Context of Respiratory Diseases and Its Importance in Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection

Angiotensin-Converting Enzyme 2 (ACE2) is an 805 amino acid protein encoded by the ACE2 gene expressed in various human cells, especially in those located in the epithelia. The primary function of ACE2 is to produce angiotensin (1–7) from angiotensin II (Ang II). The current research has described the importance of ACE2 and Ang (1–7) in alternative routes of the renin-angiotensin system (RAS) that promote the downregulation of fibrosis, inflammation, and oxidative stress processes in a great variety of diseases, such as hypertension, acute lung injury, liver cirrhosis, and kidney abnormalities. Investigations into the recent outbreak of the new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have revealed the importance of ACE2 during infection and its role in recognizing viral binding proteins through interactions with specific amino acids of this enzyme. Additionally, the ACE2 expression in several organs has allowed us to understand the clinical picture related to the infection caused by SARS-CoV-2. This review aims to provide context for the functions and importance of ACE2 with regards to SARS-CoV-2 in the general clinical aspect and its impact on other diseases, especially respiratory diseases.