The ApoE Locus and COVID-19: Are We Going Where We Have Been?
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ABSTRACT:
SUBMITTER: Finch CE
PROVIDER: S-EPMC7454416 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The COVID-19 pandemic has infected over 25 million of people worldwide, 5% of whom evolved to death and, among of the active cases, more than 60 thousand are classified as critical or severe. Recent studies revealed that ApoE, a protein encoded by APOE gene, may increase the risk of severe COVID-19 cases. ApoE has been involved with prevention of tissue damage and promotion of adaptative immune response in the lungs. This study investigated frequencies distribution of alleles that alter the ApoE expression in lung tissues to trace a profile of these variants and associate them to COVID-19 clinical outcomes. Data about APOE expression levels was obtained from the Genotype-Tissue Expression Project and the allele frequencies of APOE variants was acquired from the populations included in the phase 3 release of the 1000 Genomes Project. A total of 128 variants showed a significant impact on the APOE expression in lung tissues (p < 0.0001). Linkage Disequilibrium analysis revealed that 98 variants were closely grouped into seven distinct haplotype blocks, of which six were composed of variants that significantly decrease APOE gene expression in the lungs. Most of the haplotypes with higher impact on APOE expression showed greater frequencies in Europeans and lower in Africans, which implies that European populations might be more susceptible to SARS-CoV-2 infection. The present study indicates a potential genetic contribution of APOE expression-modifying variants in modulating the prognosis of COVID-19.
| S-EPMC8220252 | biostudies-literature
Project description:The severity of the COVID-19 pandemic and the pace of its global spread have motivated researchers to opt for repurposing existing drugs against SARS-CoV-2 rather than discover or develop novel ones. For reasons of speed, throughput, and cost-effectiveness, virtual screening campaigns, relying heavily on in silico docking, have dominated published reports. A particular focus as a drug target has been the principal active site (i.e., RNA synthesis) of RNA-dependent RNA polymerase (RdRp), despite the existence of a second, and also indispensable, active site in the same enzyme. Here we report the results of our experimental interrogation of several small-molecule inhibitors, including natural products proposed to be effective by in silico studies. Notably, we find that two antibiotics in clinical use, fidaxomicin and rifabutin, inhibit RNA synthesis by SARS-CoV-2 RdRp in vitro and inhibit viral replication in cell culture. However, our mutagenesis studies contradict the binding sites predicted computationally. We discuss the implications of these and other findings for computational studies predicting the binding of ligands to large and flexible protein complexes and therefore for drug discovery or repurposing efforts utilizing such studies. Finally, we suggest several improvements on such efforts ongoing against SARS-CoV-2 and future pathogens as they arise.
| S-EPMC9228142 | biostudies-literature
Project description:We performed single cell RNA-sequencing of lungs from APOE knock-in mice in the absence of infection or four days post infection with SARS-CoV-2 MA10. Infected mice showed major remodeling of the cellular composition with expansion of myeloid cells and relative depletion of epithelial cells. In infected mice, APOE2 mice showed enrichment of pathways implicated in immune activation, consistent with immunologic misfiring.
2022-08-07 | GSE199498 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2022-08-07 | GSE184289 | GEO
Project description: Not available
| S-BSST563 | biostudies-other
Project description:The apolipoprotein E (APOE) gene on chromosome 19q13.32, was the first, and remains the strongest, genetic risk factor for Alzheimer's disease (AD). Additional signals associated with AD have been located in chromosome 19, including ABCA7 (19p13.3) and CD33 (19q13.41). The ABCA7 gene has been replicated in most populations. However, the contribution to AD of other signals close to APOE gene remains controversial. Possible explanations for inconsistency between reports include long range linkage disequilibrium (LRLD). We analysed the contribution of ABCA7 and CD33 loci to AD risk and explore LRLD patterns across APOE region. To evaluate AD risk conferred by ABCA7 rs4147929:G>A and CD33 rs3865444:C>A, we used a large Spanish population (1796 AD cases, 2642 controls). The ABCA7 rs4147929:G>A SNP effect was nominally replicated in the Spanish cohort and reached genome-wide significance after meta-analysis (odds ratio (OR)=1.15, 95% confidence interval (95% CI)=1.12-1.19; P = 1.60 x 10-19). CD33 rs3865444:C>A was not associated with AD in the dataset. The meta-analysis was also negative (OR=0.98, 95% CI=0.93-1.04; P=0.48). After exploring LRLD patterns between APOE and CD33 in several datasets, we found significant LD (D' >0.20; P <0.030) between APOE-?2 and CD33 rs3865444C>A in two of five datasets, suggesting the presence of a non-universal long range interaction between these loci affecting to some populations. In conclusion, we provide here evidence of genetic association of the ABCA7 locus in the Spanish population and also propose a plausible explanation for the controversy on the contribution of CD33 to AD susceptibility.
| S-EPMC5973862 | biostudies-literature
Project description:Objective This study assesses the impact of coronavirus disease 2019 (COVID-19) on the pattern of neurological emergencies reaching a tertiary care center. Materials and Methods This is a retrospective and single center study involving 295 patients with neurological emergencies mainly including acute stroke, status epilepticus (SE), and tubercular meningitis visiting emergency department (ED) from January 1 to April 30, 2020 and divided into pre- and during lockdown, the latter starting from March 25 onward. The primary outcome was number of neurological emergencies visiting ED per week in both periods. Secondary outcomes included disease severity at admission, need for mechanical ventilation (MV), delay in hospitalization, in-hospital mortality, and reasons for poor compliance to ongoing treatment multivariate binary logistic regression was used to find independent predictors of in-hospital mortality which included variables with p <0.1 on univariate analysis. Structural break in the time series analysis was done by using Chow test. Results There was 53.8% reduction in number of neurological emergencies visiting ED during lockdown (22.1 visits vs. 10.2 visits per week, p = 0.001), significantly affecting rural population ( p = 0.004). Presenting patients had comparatively severe illness with increased requirement of MV ( p < 0.001) and significant delay in hospitalization during lockdown ( p < 0.001). Poor compliance to ongoing therapy increased from 34.4% in pre-lockdown to 64.7% patients during lockdown ( p < 0.001), mostly due to nonavailability of drugs ( p < 0.001). Overall, 35 deaths were recorded, with 20 (8.2%) in pre-lockdown and 15 (29.4%) during lockdown ( p = 0.001). Lockdown, nonavailability of local health care, delay in hospitalization, severity at admission, and need for MV emerged as independent predictors of poor outcome in stroke and delay in hospitalization in SE. Conclusion COVID-19 pandemic and associated lockdown resulted in marked decline in non-COVID neurological emergencies reporting to ED, with more severe presentations and significant delay from onset of symptoms to hospitalization.
| S-EPMC8289548 | biostudies-literature
Project description:Here we analyze the transcriptional profiles of homogenized lungs resected from young female APOE2, APOE3, and APOE4 knock-in mice on day 4 post infection with SARS-CoV-2 MA10. Weighted gene co-expression analysis identified gene modules enriched for genes implicated in T and B cell activation to be downregulated in APOE2 and APOE4 mice during COVID-19 progression.
2022-08-07 | GSE200132 | GEO
Project description:Here we analyze the transcriptional profiles of homogenized lungs resected from APOE2, APOE3, and APOE4 knock-in mice on day 4 post infection with SARS-CoV-2 MA10. This experiment validated a prior RNA-seq experiment revealing blunted adaptive immunity in APOE2 and APOE4 mice during COVID-19 progression.
2022-08-07 | GSE184288 | GEO
Project description:Here we analyze the transcriptional profiles of homogenized lungs resected from APOE2, APOE3, and APOE4 knock-in mice in the absence of infection (day 0) and on days 2 and 4 post infection with SARS-CoV-2 MA10. Weighted gene co-expression analysis identified gene modules enriched for genes implicated in T and B cell activation to be downregulated in APOE2 and APOE4 mice during COVID-19 progression.
2022-08-07 | GSE184287 | GEO