SARS-CoV-2 infections and COVID-19 mortalities strongly correlate with ACE1 I/D genotype.
TL;DR: Analysis of genetic factors associated with SARS-CoV-2 infection with a focus on angiotensin-converting enzyme (ACE)-related genes suggests that the ACE1 II genotype may influence the prevalence and clinical outcome of CO VID-19 and serve as a predictive marker for COVID-19 risk and severity.
About: This article is published in Gene.The article was published on 2020-07-03 and is currently open access. It has received 108 citations till now. The article focuses on the topics: Middle East respiratory syndrome & Genotype frequency.
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TL;DR: IL-6 is a nexus for immune responses and disease and its role in vaccine selection and wound healing is under investigation.
Abstract: IL-6 is involved both in immune responses and in inflammation, hematopoiesis, bone metabolism and embryonic development. IL-6 plays roles in chronic inflammation (closely related to chronic inflammatory diseases, autoimmune diseases and cancer) and even in the cytokine storm of corona virus disease 2019 (COVID-19). Acute inflammation during the immune response and wound healing is a well-controlled response, whereas chronic inflammation and the cytokine storm are uncontrolled inflammatory responses. Non-immune and immune cells, cytokines such as IL-1β, IL-6 and tumor necrosis factor alpha (TNFα) and transcription factors nuclear factor-kappa B (NF-κB) and signal transducer and activator of transcription 3 (STAT3) play central roles in inflammation. Synergistic interactions between NF-κB and STAT3 induce the hyper-activation of NF-κB followed by the production of various inflammatory cytokines. Because IL-6 is an NF-κB target, simultaneous activation of NF-κB and STAT3 in non-immune cells triggers a positive feedback loop of NF-κB activation by the IL-6-STAT3 axis. This positive feedback loop is called the IL-6 amplifier (IL-6 Amp) and is a key player in the local initiation model, which states that local initiators, such as senescence, obesity, stressors, infection, injury and smoking, trigger diseases by promoting interactions between non-immune cells and immune cells. This model counters dogma that holds that autoimmunity and oncogenesis are triggered by the breakdown of tissue-specific immune tolerance and oncogenic mutations, respectively. The IL-6 Amp is activated by a variety of local initiators, demonstrating that the IL-6-STAT3 axis is a critical target for treating diseases.
326 citations
TL;DR: In this paper, the authors reviewed the existing literature and knowledge of ACE2 in COVID-19 setting and focused on its pathophysiologic involvement in disease progression, clinical outcomes, and therapeutic potential.
Abstract: COVID-19 pandemic is caused by the novel coronavirus SARS-CoV-2. Angiotensin-converting enzyme 2 (ACE2) is not only an enzyme but also a functional receptor on cell surfaces through which SARS-CoV-2 enters the host cells and is highly expressed in the heart, kidneys, and lungs and shed into the plasma. ACE2 is a key regulator of the renin-angiotensin-aldosterone system (RAAS). SARS-CoV-2 causes ACE/ACE2 balance disruption and RAAS activation, which leads ultimately to COVID-19 progression, especially in patients with comorbidities, such as hypertension, diabetes mellitus, and cardiovascular disease. Therefore, ACE2 expression may have paradoxical effects, aiding SARS-CoV-2 pathogenicity, yet conversely limiting viral infection. This article reviews the existing literature and knowledge of ACE2 in COVID-19 setting and focuses on its pathophysiologic involvement in disease progression, clinical outcomes, and therapeutic potential.
325 citations
TL;DR: An adverse outcome of COVID-19 was associated with male gender, hypertension, hypercholesterolemia and the ACE1 genotype, and the effect was dependent on the hypertensive status.
136 citations
TL;DR: In this paper , the authors analyzed and compared the alterations of SARS-CoV-2 S RNA sequences in the defined variants (Alpha to Omicron), and observed some interesting findings regarding the S1-RBD/S2 mutation/deletion equilibrium that maybe affect and modify its activity.
85 citations
TL;DR: The dynamics of the pandemic shows that the problems of the new coronavirus can be overcome due to people's awareness of the epidemics, rational viral diagnostics and a high level of medical care.
61 citations
Cites background from "SARS-CoV-2 infections and COVID-19 ..."
...Very recently, we showed a strong negative correlation that the numbers of SARS-CoV-2 infected cases and deaths due to viral infection decreased with increasing ACE1 II genotype frequency [19]....
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...Therefore, in the I/D polymorphism, there are three different genotypes, II, ID and DD. ACE1 is a metalloproteinase, which is a type I transmembrane glycoprotein....
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...This can further reduce the effects of ACE2, which counteracts the pathophysiological effects of Ang II produced by ACE1, and may worsen the pathology....
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...Thus, the ACE1/ACE2 imbalance predicts that COVID-19 patients with the D allele of ACE1, especially the DD genotype, have a higher severity and prevalence of COVID-19....
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...The human Angiotensin-converting enzyme 1 (ACE1) gene on chromosome 17 has an insertion (I) or deletion (D) of a 287 base pair (bp) Alu repeat sequence in intron 16 [18]....
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References
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TL;DR: Human airway epithelial cells were used to isolate a novel coronavirus, named 2019-nCoV, which formed a clade within the subgenus sarbecovirus, Orthocoronavirinae subfamily, which is the seventh member of the family of coronaviruses that infect humans.
Abstract: In December 2019, a cluster of patients with pneumonia of unknown cause was linked to a seafood wholesale market in Wuhan, China. A previously unknown betacoronavirus was discovered through the use of unbiased sequencing in samples from patients with pneumonia. Human airway epithelial cells were used to isolate a novel coronavirus, named 2019-nCoV, which formed a clade within the subgenus sarbecovirus, Orthocoronavirinae subfamily. Different from both MERS-CoV and SARS-CoV, 2019-nCoV is the seventh member of the family of coronaviruses that infect humans. Enhanced surveillance and further investigation are ongoing. (Funded by the National Key Research and Development Program of China and the National Major Project for Control and Prevention of Infectious Disease in China.).
21,455 citations
TL;DR: It is demonstrated that SARS-CoV-2 uses the SARS -CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming, and it is shown that the sera from convalescent SARS patients cross-neutralized Sars-2-S-driven entry.
15,362 citations
"SARS-CoV-2 infections and COVID-19 ..." refers background in this paper
...Moreover, because ACE2 is a receptor for SARS-COV-2 (Hoffmann et al., 2020), viral infection may lead to the suppression of ACE2 function and cause ACE1/ACE2 imbalance responsible for RAAS over-activation and pulmonary shutdown (Gemmati et al., 2020)....
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...The angiotensin-converting enzyme (ACE) 2, a host cell receptor for SARS-CoV-2 (Hoffmann et al., 2020), has an analog called ACE1, and these https://doi.org/10.1016/j.gene.2020.144944 Received 26 June 2020; Accepted 1 July 2020 Abbreviations: SARS-CoV-2, severe acute respiratory syndrome…...
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...…genes, ACE2, cathepsin L (CTSL) and transmembrane serine protease 2 (TMPRSS2) likely to be involved in the infection/pathogenicity of SARS-CoV-2 (Hoffmann et al., 2020; Ou et al., 2020), from the Genome Aggregation Database (gnomAD) (https://gnomad.broadinstitute.org/). gnomAD summarizes the…...
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TL;DR: The insertion/deletion polymorphism accounted for 47% of the total phenotypic variance of serum ACE, showing that the ACE gene locus is the major locus that determines serum ACE concentration.
Abstract: A polymorphism consisting of the presence or absence of a 250-bp DNA fragment was detected within the angiotensin I-converting enzyme gene (ACE) using the endothelial ACE cDNA probe. This polymorphism was used as a marker genotype in a study involving 80 healthy subjects, whose serum ACE levels were concomitantly measured. Allele frequencies were 0.6 for the shorter allele and 0.4 for the longer allele. A marked difference in serum ACE levels was observed between subjects in each of the three ACE genotype classes. Serum immunoreactive ACE concentrations were, respectively, 299.3 +/- 49, 392.6 +/- 66.8, and 494.1 +/- 88.3 micrograms/liter, for homozygotes with the longer allele (n = 14), and heterozygotes (n = 37) and homozygotes (n = 29) with the shorter allele. The insertion/deletion polymorphism accounted for 47% of the total phenotypic variance of serum ACE, showing that the ACE gene locus is the major locus that determines serum ACE concentration. Concomitant determination of the ACE genotype will improve discrimination between normal and abnormal serum ACE values by allowing comparison with a more appropriate reference interval.
3,745 citations
TL;DR: The complete genomic sequence of DCP1 is presented, representing the longest contiguous scan for sequence variation in human DNA and raising important issues for the determination of functional DNA variants within genes and genetic studies in humans based on marker association.
Abstract: Angiotensin converting enzyme (encoded by the gene DCP1, also known as ACE) catalyses the conversion of angiotensin I to the physiologically active peptide angiotensin II, which controls fluid-electrolyte balance and systemic blood pressure. Because of its key function in the renin-angiotensin system, many association studies have been performed with DCP1. Nearly all studies have associated the presence (insertion, I) or absence (deletion, D) of a 287-bp Alu repeat element in intron 16 with the levels of circulating enzyme or cardiovascular pathophysiologies1,2,3. Many epidemiological studies suggest that the DCP1*D allele confers increased susceptibility to cardiovascular disease; however, other reports have found no such association or even a beneficial effect (refs 4, 5, 6, 7). We present here the complete genomic sequence of DCP1 from 11 individuals, representing the longest contiguous scan (24 kb) for sequence variation in human DNA. We identified 78 varying sites in 22 chromosomes that resolved into 13 distinct haplotypes. Of the variant sites, 17 were in absolute linkage disequilibrium with the commonly typed Alu insertion/deletion polymorphism, producing two distinct and distantly related clades. We also identified a major subdivision in the Alu deletion clade that enables further analysis of the traits associated with this gene. The diversity uncovered in DCP1 is comparable to that described for other regions in the human genome8,9,10,11. The highly correlated structure in DCP1 raises important issues for the determination of functional DNA variants within genes and genetic studies in humans based on marker association.
497 citations
TL;DR: Genetic variability across the three major histocompatibility complex (MHC) class I genes may affect susceptibility to and severity of the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronav virus disease 2019 (COVID-19), and the potential for cross-protective immunity conferred by prior exposure to four common human coronaviruses.
Abstract: Genetic variability across the three major histocompatibility complex (MHC) class I genes (human leukocyte antigen A [HLA-A], -B, and -C genes) may affect susceptibility to and severity of the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19). We performed a comprehensive in silico analysis of viral peptide-MHC class I binding affinity across 145 HLA-A, -B, and -C genotypes for all SARS-CoV-2 peptides. We further explored the potential for cross-protective immunity conferred by prior exposure to four common human coronaviruses. The SARS-CoV-2 proteome was successfully sampled and was represented by a diversity of HLA alleles. However, we found that HLA-B*46:01 had the fewest predicted binding peptides for SARS-CoV-2, suggesting that individuals with this allele may be particularly vulnerable to COVID-19, as they were previously shown to be for SARS (M. Lin, H.-T. Tseng, J. A. Trejaut, H.-L. Lee, et al., BMC Med Genet 4:9, 2003, https://bmcmedgenet.biomedcentral.com/articles/10.1186/1471-2350-4-9). Conversely, we found that HLA-B*15:03 showed the greatest capacity to present highly conserved SARS-CoV-2 peptides that are shared among common human coronaviruses, suggesting that it could enable cross-protective T-cell-based immunity. Finally, we reported global distributions of HLA types with potential epidemiological ramifications in the setting of the current pandemic.IMPORTANCE Individual genetic variation may help to explain different immune responses to a virus across a population. In particular, understanding how variation in HLA may affect the course of COVID-19 could help identify individuals at higher risk from the disease. HLA typing can be fast and inexpensive. Pairing HLA typing with COVID-19 testing where feasible could improve assessment of severity of viral disease in the population. Following the development of a vaccine against SARS-CoV-2, the virus that causes COVID-19, individuals with high-risk HLA types could be prioritized for vaccination.
418 citations