scholarly journals Analysis of ACE2 Genetic Variability Among Populations Highlights A Possible Link With COVID19-Related Neurological Complications

2020 ◽  
Author(s):  
Claudia Strafella ◽  
Valerio Caputo ◽  
Andrea Termine ◽  
Shila Barati ◽  
Stefano Gambardella ◽  
...  
Keyword(s):  
Genetic Variability ◽  
Treatment Strategies ◽  
Neurological Complications ◽  
Copy Number Variations ◽  
Neurological Involvement ◽  
The Novel ◽  
Single Nucleotide Variants ◽  
Angiotensin Converting Enzyme 2 ◽  
Related Phenotype ◽  
Entry Receptor

Abstract The Angiotensin-converting enzyme 2 (ACE2) has been recently recognized as the entry receptor of the novel pathogenic Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-Cov-2). The presence of structural and sequence variants in ACE2 gene may affect its expression in different tissues and determine a differential response to SARS-Cov-2 infection and COVID19-related phenotype. The present study investigated the genetic variability of ACE2 in terms of Single Nucleotide Variants (SNVs), Copy Number Variations (CNVs) and expression Quantitative Loci (eQTLs) in a cohort of 268 individuals representative of the Italian general population. The analysis identified 5 SNVs (rs35803318, rs41303171, rs774469453, rs773676270, rs2285666) which displayed a significantly different frequency distribution in the Italian cohort compared to the worldwide populations. The analysis of eQTLs located in and targeting ACE2, revealed a high distribution of eQTL variants in different brain tissues, suggesting a possible link between the genetic variability of ACE2 and the neurological complications in patients with COVID19. Further research is needed to clarify the possible relationship between ACE2 expression and the susceptibility to neurological complications in patients with COVID19. In fact, patients at higher risk of neurological involvement may need different monitoring and treatment strategies in order to prevent severe, permanent brain injury.

scholarly journals Analysis of ACE2 Genetic Variability among Populations Highlights a Possible Link with COVID-19-Related Neurological Complications

Genes ◽  
2020 ◽  
Vol 11 (7) ◽  
pp. 741 ◽  
Author(s):  
Claudia Strafella ◽  
Valerio Caputo ◽  
Andrea Termine ◽  
Shila Barati ◽  
Stefano Gambardella ◽  
...  
Keyword(s):  
Genetic Variability ◽  
Treatment Strategies ◽  
Neurological Complications ◽  
Copy Number Variations ◽  
Neurological Involvement ◽  
Italian Population ◽  
Single Nucleotide Variants ◽  
Angiotensin Converting Enzyme 2 ◽  
Worldwide Population ◽  
Related Phenotype

Angiotensin-converting enzyme 2 (ACE2) has been recognized as the entry receptor of the novel severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2). Structural and sequence variants in ACE2 gene may affect its expression in different tissues and determine a differential response to SARS-Cov-2 infection and the COVID-19-related phenotype. The present study investigated the genetic variability of ACE2 in terms of single nucleotide variants (SNVs), copy number variations (CNVs), and expression quantitative loci (eQTLs) in a cohort of 268 individuals representative of the general Italian population. The analysis identified five SNVs (rs35803318, rs41303171, rs774469453, rs773676270, and rs2285666) in the Italian cohort. Of them, rs35803318 and rs2285666 displayed a significant different frequency distribution in the Italian population with respect to worldwide population. The eQTLs analysis located in and targeting ACE2 revealed a high distribution of eQTL variants in different brain tissues, suggesting a possible link between ACE2 genetic variability and the neurological complications in patients with COVID-19. Further research is needed to clarify the possible relationship between ACE2 expression and the susceptibility to neurological complications in patients with COVID-19. In fact, patients at higher risk of neurological involvement may need different monitoring and treatment strategies in order to prevent severe, permanent brain injury.

scholarly journals High affinity binding of SARS-CoV-2 spike protein enhances ACE2 carboxypeptidase activity

2020 ◽  
Vol 295 (52) ◽  
pp. 18579-18588 ◽  
Author(s):  
Jinghua Lu ◽  
Peter D. Sun
Keyword(s):  
Spike Protein ◽  
The Novel ◽  
Global Public Health ◽  
Health Crisis ◽  
Peptide Substrates ◽  
Angiotensin Converting Enzyme 2 ◽  
High Affinity ◽  
Enzymatic Function ◽  
Biological Substrates ◽  
Entry Receptor

The novel severe acute respiratory syndrome coronavirus (SARS-CoV-2) has emerged to a pandemic and caused global public health crisis. Human angiotensin-converting enzyme 2(ACE2) was identified as the entry receptor for SARS-CoV-2. As a carboxypeptidase, ACE2 cleaves many biological substrates besides angiotensin II to control vasodilatation and vascular permeability. Given the nanomolar high affinity between ACE2 and SARS-CoV-2 spike protein, we investigated how this interaction would affect the enzymatic activity of ACE2. Surprisingly, SARS-CoV-2 trimeric spike protein increased ACE2 proteolytic activity ∼3-10 fold against model peptide substrates, such as caspase-1 substrate and Bradykinin-analog. The enhancement in ACE2 enzymatic function was mediated by the binding of SARS-CoV-2 spike RBD domain. These results highlighted the potential for SARS-CoV-2 infection to enhance ACE2 activity, which may be relevant to the cardiovascular symptoms associated with COVID-19.

scholarly journals Genetic analysis of the novel SARS-CoV-2 host receptor TMPRSS2 in different populations

2020 ◽  
Author(s):  
Roberta Russo ◽  
Immacolata Andolfo ◽  
Vito Alessandro Lasorsa ◽  
Achille Iolascon ◽  
Mario Capasso
Keyword(s):  
Differential Susceptibility ◽  
Cellular Level ◽  
The Novel ◽  
Coding Region ◽  
Angiotensin Converting Enzyme 2 ◽  
Viral Spread ◽  
Viral Particles ◽  
Cellular Antiviral Response ◽  
Different Populations ◽  
Entry Receptor

AbstractThe infection coronavirus disease 2019 (COVID-19) is caused by a virus classified as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). At cellular level, virus infection initiates with binding of viral particles to the host surface cellular receptor angiotensin converting enzyme 2 (ACE2). SARS-CoV-2 engages ACE2 as the entry receptor and employs the cellular serine protease 2 (TMPRSS2) for S protein priming. TMPRSS2 activity is essential for viral spread and pathogenesis in the infected host. Understanding how TMPRSS2 protein expression in the lung varies in the population could reveal important insights into differential susceptibility to influenza and coronavirus infections. Here, we systematically analyzed coding-region variants in TMPRSS2 and the eQTL variants, which may affect the gene expression, to compare the genomic characteristics of TMPRSS2 among different populations. Our findings suggest that the lung-specific eQTL variants may confer different susceptibility or response to SARS-CoV-2 infection from different populations under the similar conditions. In particular, we found that the eQTL variant rs35074065 is associated with high expression of TMPRSS2 but with a low expression of the interferon (IFN)-α/β-inducible gene, MX1, splicing isoform. Thus, these subjects could account for a more susceptibility either to viral infection or to a decrease in cellular antiviral response.

scholarly journals Tissue-specific and interferon-inducible expression of non-functional ACE2 through endogenous retrovirus co-option

2020 ◽  
Author(s):  
Kevin Ng ◽  
Jan Attig ◽  
William Bolland ◽  
George R. Young ◽  
Jack Major ◽  
...  
Keyword(s):  
De Novo ◽  
Expression Patterns ◽  
Endogenous Retrovirus ◽  
The Novel ◽  
Specific Expression ◽  
Angiotensin Converting Enzyme 2 ◽  
Viral Spread ◽  
Novel Transcript ◽  
Physiological Processes ◽  
Entry Receptor

SummaryAngiotensin-converting enzyme 2 (ACE2) is an entry receptor for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), as well as a regulator of several physiological processes. ACE2 has recently been proposed to be interferon-inducible, suggesting that SARS-CoV-2 may exploit this phenomenon to enhance viral spread and questioning the efficacy of interferon treatment in Coronavirus disease 2019 (COVID-19). Using a recent de novo transcript assembly that captured previously unannotated transcripts, we describe a novel isoform of ACE2, generated by co-option of an intronic long terminal repeat (LTR) retroelement promoter. The novel transcript, termed LTR16A1-ACE2, exhibits specific expression patterns across the aerodigestive and gastrointestinal tracts and, importantly, is highly responsive to interferon stimulation. In stark contrast, expression of canonical ACE2 is completely unresponsive to interferon stimulation. Moreover, the LTR16A1-ACE2 translation product is a truncated, unstable ACE2 form, lacking domains required for SARS-CoV-2 binding and therefore unlikely to contribute to or enhance viral infection.

scholarly journals Neurological Involvement of Coronavirus Disease 2019: A Systematic Review

2020 ◽  
Author(s):  
Malik Ghannam ◽  
Qasem Alshaer ◽  
Mustafa Al-Chalabi ◽  
Lara Zakarna ◽  
Jetter Robertson ◽  
...  
Keyword(s):  
Neuromuscular Disorders ◽  
Treatment Options ◽  
Neurological Complications ◽  
Neurological Involvement ◽  
The Novel ◽  
Clinical Observations ◽  
Ovid Medline ◽  
Novel Coronavirus ◽  
Meta Analyses ◽  
Test Treatment

Abstract Background: In December 2019, unexplained cases of pneumonia emerged in Wuhan, China, which were found to be secondary to the novel coronavirus SARS-CoV-2. On March 11, 2020, the WHO declared the Coronavirus Disease 2019 (COVID-2019) outbreak, a pandemic. Although the most common presentations of COVID-19 are fever, cough and shortness of breath, several clinical observations indicate that COVID-19 does affect the central and peripheral nervous system. Methods: We conducted a systematic literature search from December 01, 2019 to May 14, 2020 using multiple combinations of keywords from PubMed and Ovid Medline databases according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We included articles with cases of COVID-19 that were evident for neurological involvement. Results: We were able to identify 82 cases of COVID-19 with neurological complications. The mean age was 62.28 years. 37.8% of the patients were women (n = 31). 48.8% of the patients (n=40) had cerebrovascular insults, 28% (n=23) had neuromuscular disorders, 18.3% of the patients (n=15) had encephalitis or encephalopathy, and 2.4% (n=2) presented with status epilepticus. Conclusions: Neurological manifestations of COVID-19 infection are not rare, especially large vessel stroke, Guillain barre syndrome and meningoencephalitis. Moving forward, further studies are needed to clarify the prevalence of the neurological complications of COVID-19, investigate their biological backgrounds, and test treatment options. Physicians should be cautious not to overlook other neurological diagnoses that can mimic COVID-19 during the pandemic.

scholarly journals Identification and monitoring of mutations in circulating cell-free tumor DNA in hepatocellular carcinoma treated with lenvatinib

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Yasutoshi Fujii ◽  
Atsushi Ono ◽  
C. Nelson Hayes ◽  
Hiroshi Aikata ◽  
Masami Yamauchi ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Biological Effects ◽  
Treatment Strategies ◽  
Progression Free Survival ◽  
Copy Number Variations ◽  
Single Nucleotide Variants ◽  
Advanced Hcc ◽  
Specificity And Sensitivity ◽  
Somatic Alterations ◽  
Tumor Dna

Abstract Background There has been a recent surge in interest in predicting biological effects associated with genomic alterations in order to implement personalized cancer treatment strategies. However, no reports have yet evaluated the utility of profiling blood-based circulating tumor DNA (ctDNA) in hepatocellular carcinoma (HCC) patients treated with lenvatinib (LEN). Method We retrospectively performed ctDNA next-generation sequencing (NGS) analysis in 24 patients with advanced HCC at baseline and 4 weeks after initiation of LEN. Association of the changes in variant allele frequencies (VAFs) during treatment and clinical outcome were evaluated. Results In total, 131 single nucleotide variants, 17 indels, and 23 copy number variations were detected as somatic alterations in 28, 6, and 12 genes, respectively in 23 of 24 patients. The most frequently altered genes were TP53 (54%), CTNNB1 (42%), TERT (42%), ATM (25%), and ARID1A (13%). The reduction in the mean frequency of variants (VAFmean) following 4 weeks of LEN treatment was associated with longer progression-free survival. The specificity and sensitivity of the reduction of VAFmean for predicting partial response were 0.67 and 1.0, respectively, which were higher than those of serum α-fetoprotein level (0.10 and 0.93, respectively). No association between the mutation status at baseline and the effectiveness of LEN was observed. Conclusion Our study demonstrated that somatic alterations could be detected in the majority of advanced HCC patients by ctDNA profiling and that ctDNA-kinetics during LEN treatment was a useful marker of disease progression. These results suggest that ctDNA profiling is a promising method that provides valuable information in clinical practice.

scholarly journals Combination of Genome-Wide Polymorphisms and Copy Number Variations of Pharmacogenes in Koreans

2021 ◽  
Vol 11 (1) ◽  
pp. 33
Author(s):  
Nayoung Han ◽  
Jung Mi Oh ◽  
In-Wha Kim
Keyword(s):  
Copy Number ◽  
Genome Wide Association Study ◽  
Copy Number Gain ◽  
Copy Number Variations ◽  
Gene Gain ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Haplotype Blocks ◽  
Genome Wide ◽  
Control And Prevention

For predicting phenotypes and executing precision medicine, combination analysis of single nucleotide variants (SNVs) genotyping with copy number variations (CNVs) is required. The aim of this study was to discover SNVs or common copy CNVs and examine the combined frequencies of SNVs and CNVs in pharmacogenes using the Korean genome and epidemiology study (KoGES), a consortium project. The genotypes (N = 72,299) and CNV data (N = 1000) were provided by the Korean National Institute of Health, Korea Centers for Disease Control and Prevention. The allele frequencies of SNVs, CNVs, and combined SNVs with CNVs were calculated and haplotype analysis was performed. CYP2D6 rs1065852 (c.100C>T, p.P34S) was the most common variant allele (48.23%). A total of 8454 haplotype blocks in 18 pharmacogenes were estimated. DMD ranked the highest in frequency for gene gain (64.52%), while TPMT ranked the highest in frequency for gene loss (51.80%). Copy number gain of CYP4F2 was observed in 22 subjects; 13 of those subjects were carriers with CYP4F2*3 gain. In the case of TPMT, approximately one-half of the participants (N = 308) had loss of the TPMT*1*1 diplotype. The frequencies of SNVs and CNVs in pharmacogenes were determined using the Korean cohort-based genome-wide association study.

scholarly journals Response of Severe EV71-Infected Patients to Hyperimmune Plasma Treatment: A Pilot Study

Pathogens ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 625
Author(s):  
Chonnamet Techasaensiri ◽  
Artit Wongsa ◽  
Thanyawee Puthanakit ◽  
Kulkanya Chokephaibulkit ◽  
Tawee Chotpitayasunondh ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Antibody Therapy ◽  
Foot And Mouth Disease ◽  
Neurological Complications ◽  
Neurological Involvement ◽  
Healthy Donors ◽  
Enterovirus A71 ◽  
Number Of Patients ◽  
Causative Agents ◽  
East And Southeast Asia

Hand, foot, and mouth disease (HFMD) is highly prevalent in East and Southeast Asia. It particularly affects children under five years of age. The most common causative agents are coxsackieviruses A6 and A16, and enterovirus A71 (EV71). The clinical presentation is usually mild and self-limited, but, in some cases, severe and fatal complications develop. To date, no specific therapy or worldwide vaccine is available. In general, viral infection invokes both antibody and cell-mediated immune responses. Passive immunity transfer can ameliorate the severe symptoms of diseases such as COVID-19, influenza, MERS, and SARS. Hyperimmune plasma (HIP) from healthy donors with high anti-EV71 neutralizing titer were used to transfuse confirmed EV71-infected children with neurological involvement (n = 6). It resulted in recovery within three days, with no neurological sequelae apparent upon examination 14 days later. Following HIP treatment, plasma chemokines were decreased, whereas anti-inflammatory and pro-inflammatory cytokines gradually increased. Interestingly, IL-6 and G-CSF levels in cerebrospinal fluid declined sharply within three days. These findings indicate that HIP has therapeutic potential for HFMD with neurological complications. However, given the small number of patients who have been treated, a larger cohort study should be undertaken. Successful outcomes would stimulate the development of anti-EV71 monoclonal antibody therapy.

scholarly journals Unsuspected somatic mosaicism for FBN1 gene contributes to Marfan syndrome

2021 ◽  
Author(s):  
Pauline Arnaud ◽  
Hélène Morel ◽  
Olivier Milleron ◽  
Laurent Gouya ◽  
Christine Francannet ◽  
...  
Keyword(s):  
Marfan Syndrome ◽  
Somatic Mosaicism ◽  
Variant Calling ◽  
Copy Number Variations ◽  
Pathogenic Variant ◽  
Single Nucleotide Variants ◽  
Bioinformatics Analyses ◽  
Single Nucleotide ◽  
Fbn1 Gene ◽  
Pathogenic Variants

Abstract Purpose Individuals with mosaic pathogenic variants in the FBN1 gene are mainly described in the course of familial screening. In the literature, almost all these mosaic individuals are asymptomatic. In this study, we report the experience of our team on more than 5,000 Marfan syndrome (MFS) probands. Methods Next-generation sequencing (NGS) capture technology allowed us to identify five cases of MFS probands who harbored a mosaic pathogenic variant in the FBN1 gene. Results These five sporadic mosaic probands displayed classical features usually seen in Marfan syndrome. Combined with the results of the literature, these rare findings concerned both single-nucleotide variants and copy-number variations. Conclusion This underestimated finding should not be overlooked in the molecular diagnosis of MFS patients and warrants an adaptation of the parameters used in bioinformatics analyses. The five present cases of symptomatic MFS probands harboring a mosaic FBN1 pathogenic variant reinforce the fact that apparently asymptomatic mosaic parents should have a complete clinical examination and a regular cardiovascular follow-up. We advise that individuals with a typical MFS for whom no single-nucleotide pathogenic variant or exon deletion/duplication was identified should be tested by NGS capture panel with an adapted variant calling analysis.

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