scholarly journals Mendelian randomisation identifies alternative splicing of the FAS death receptor as a mediator of severe COVID-19

2021 ◽  
Author(s):  
Lucija Klaric ◽  
Jack S Gisby ◽  
Artemis Papadaki ◽  
Marisa D Muckian ◽  
Erin Macdonald-Dunlop ◽  
...  
Keyword(s):  
Fas Ligand ◽  
Meta Analysis ◽  
Severe Disease ◽  
Death Receptor ◽  
Sensitivity Analyses ◽  
Mendelian Randomisation ◽  
Protein Biomarkers ◽  
Soluble Fas ◽  
Promising Therapeutic Target ◽  
Association Data

Severe COVID-19 is characterised by immunopathology and epithelial injury. Proteomic studies have identified circulating proteins that are biomarkers of severe COVID-19, but cannot distinguish correlation from causation. To address this, we performed Mendelian randomisation (MR) to identify proteins that mediate severe COVID-19. Using protein quantitative trait loci (pQTL) data from the SCALLOP consortium, involving meta-analysis of up to 26,494 individuals, and COVID-19 genome-wide association data from the Host Genetics Initiative, we performed MR for 157 COVID-19 severity protein biomarkers. We identified significant MR results for five proteins: FAS, TNFRSF10A, CCL2, EPHB4 and LGALS9. Further evaluation of these candidates using sensitivity analyses and colocalization testing provided strong evidence to implicate the apoptosis-associated cytokine receptor FAS as a causal mediator of severe COVID-19. This effect was specific to severe disease. Using RNA-seq data from 4,778 individuals, we demonstrate that the pQTL at the FAS locus results from genetically influenced alternate splicing causing skipping of exon 6. We show that the risk allele for very severe COVID-19 increases the proportion of transcripts lacking exon 6, and thereby increases soluble FAS. Soluble FAS acts as a decoy receptor for FAS-ligand, inhibiting apoptosis induced through membrane-bound FAS. In summary, we demonstrate a novel genetic mechanism that contributes to risk of severe of COVID-19, highlighting a pathway that may be a promising therapeutic target.

scholarly journals Non-Causal Effects of Asthma on COVID-19 Susceptibility and Severity

2022 ◽  
Vol 12 ◽  
Author(s):  
Li-Juan Qiu ◽  
Kang-Jia Yin ◽  
Gui-Xia Pan ◽  
Jing Ni ◽  
Bin Wang
Keyword(s):  
Severe Asthma ◽  
Genome Wide Association Study ◽  
Meta Analysis ◽  
Severe Disease ◽  
Causal Effects ◽  
Sensitivity Analyses ◽  
European Ancestry ◽  
Genome Wide ◽  
Inverse Variance ◽  
Increased Risk

Background: Asthma is observationally associated with an increased risk of COVID-19, but the causality remains unclear. We aim to determine whether there is a casual role of asthma in susceptibility to SARS-CoV-2 infection or COVID-19 severity.Methods: Instrumental variables (IVs) for asthma and moderate-to-severe asthma were obtained from publicly available summary statistics from the most recent and largest genome-wide association study (GWAS), including 394 283 and 57 695 participants of European ancestry, respectively. The corresponding data for COVID-19 susceptibility, hospitalization and severe-disease were derived from the COVID-19 Host Genetics Initiative GWAS meta-analysis of up to 1 683 768 individuals of European descent. Causality was inferred between correlated traits by Mendelian Randomization analyses. Inverse-variance weighted method was used as the primary MR estimates and multiple alternate approaches and several sensitivity analyses were also conducted.Results: Our MR analysis revealed no causal effects of asthma on COVID-19 susceptibility, hospitalization or severe disease, with odds ratio (OR) of 0.994 (95% CI: 0.962–1.027), 1.020 (95% CI: 0.955–1.089), and 0.929 (95% CI: 0.836–1.032), respectively. Furthermore, using genetic variants for moderate-to-severe asthma, a similar pattern of results was observed for COVID-19 susceptibility (OR: 0.988, 95% CI: 0.946–1.031), hospitalization (OR: 0.967, 95% CI: 0.906–1.031), and severe disease (OR: 0.911, 95% CI: 0.823–1.009). The association of asthma and moderate-to-severe asthma with COVID-19 was overall robust to sensitivity analyses.Conclusion: Genetically predicted asthma was not associated with susceptibility to, or severity of, COVID-19 disease, indicating that asthma is unlikely to be a causal factor in the development of COVID-19.

scholarly journals Estimating the causal effect of hearing loss on Alzheimer’s disease: a Mendelian randomisation study

2020 ◽  
Author(s):  
Benjamin M Jacobs ◽  
Alastair J Noyce ◽  
Christopher JD Hardy ◽  
Jason D Warren ◽  
Charles R Marshall
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Hearing Loss ◽  
Causal Effect ◽  
Meta Analysis ◽  
Sensitivity Analyses ◽  
Mendelian Randomisation ◽  
Summary Statistics ◽  
Age Related ◽  
Hearing Difficulty

AbstractBackgroundHearing loss has been identified as one of the most important risk factors for Alzheimer’s disease (AD). However, the causality of this association has not been established.MethodsWe used publicly available GWAS summary statistics to construct instrumental variables for age-related hearing difficulty. We tested these genetic instruments for association with the outcome of AD using AD GWAS summary statistics in a two-sample Mendelian randomisation analysis. We used inverse-variance weighted meta-analysis to estimate the causal effect of hearing-related traits on AD, followed by secondary sensitivity analyses including a mixture of experts approach.ResultsThere was no strong evidence for a causal relationship between genetically-determined hearing difficulty (ORFE-IVW 1.27, 95% CI 0.89 to 1.82, p=0.189) and AD risk. There was no evidence to suggest that unbalanced horizontal pleiotropy was biasing the result. Power calculations indicated our instruments were sufficiently powered to detect the magnitude of effect described in case-control and cohort settings.ConclusionsOur results suggest that the size of the observed relationship between hearing loss and AD cannot be completely accounted for by a direct causal influence. Hearing loss may have more utility as a risk marker for AD than as a modifiable risk factor.

scholarly journals Prognostic and therapeutic role of vitamin D in COVID-19: systematic review and meta-analysis

2021 ◽  
Author(s):  
Harsha Anuruddhika Dissanayake ◽  
Nipun Lakshitha de Silva ◽  
Manilka Sumanatilleke ◽  
Sawanawadu Dilantha Neomal de Silva ◽  
Kavinga Kalhari Kobawaka Gamage ◽  
...  
Keyword(s):  
Vitamin D ◽  
High Risk ◽  
Vitamin D Deficiency ◽  
Observational Studies ◽  
Meta Analysis ◽  
Severe Disease ◽  
Risk Of Bias ◽  
Sensitivity Analyses ◽  
Cochrane Library

Abstract Purpose Vitamin D deficiency/insufficiency may increase the susceptibility to COVID-19. We aimed to determine the association between vitamin D deficiency/insufficiency and susceptibility to COVID-19, its severity, mortality and role of vitamin D in its treatment. Methods We searched CINHAL, Cochrane library, EMBASE, PubMED, Scopus, and Web of Science up to 30.05.2021 for observational studies on association between vitamin D deficiency/insufficiency and susceptibility to COVID-19, severe disease and death among adults, and, randomized controlled trials (RCTs) comparing vitamin D treatment against standard care or placebo, in improving severity or mortality among adults with COVID-19. Risk of bias was assessed using Newcastle-Ottawa scale for observational studies and AUB-KQ1 Cochrane tool for RCTs. Study-level data were analyzed using RevMan 5.3 and R (v4∙1∙0). Heterogeneity was determined by I  2 and sources were explored through pre-specified sensitivity analyses, subgroup analyses and meta-regressions. Results Of 1877 search results, 76 studies satisfying eligibility criteria were included. Seventy-two observational studies were included in the meta-analysis (n=1976099). Vitamin D deficiency/insufficiency increased the odds of developing COVID-19 (OR 1∙46, 95% CI 1∙28–1∙65, p<0∙0001, I  2=92%), severe disease (OR 1∙90, 95% CI 1∙52–2∙38, p<0.0001, I  2=81%) and death (OR 2∙07, 95% CI 1∙28–3∙35, p=0.003, I  2=73%). 25-hydroxy vitamin D (25(OH)D) concentration were lower in individuals with COVID-19 compared to controls (mean difference [MD] -3∙85 ng/mL, 95% CI -5∙44,-2∙26, p=<0.0001), in patients with severe COVID-19 compared to controls with non-severe COVID19 (MD -4∙84 ng/mL, 95% CI -7∙32,-2∙35, p=0∙0001) and in non-survivors compared to survivors (MD -4∙80 ng/mL, 95%-CI -7∙89,-1∙71, p=0∙002). The association between vitamin D deficiency/insufficiency and death was insignificant when studies with high risk of bias or studies reporting unadjusted effect estimates were excluded. Risk of bias and heterogeneity were high across all analyses. Discrepancies in timing of vitamin D testing, definitions of severe COVID-19 and vitamin D deficiency/insufficiency partly explained the heterogeneity. Four RCTs were widely heterogeneous precluding meta-analysis. Conclusion Multiple observational studies involving nearly two million adults suggest vitamin D deficiency/insufficiency increases susceptibility to COVID-19 and severe COVID-19, although with a high risk of bias and heterogeneity. Association with mortality was less robust. Heterogeneity in RCTs precluded their meta-analysis.

scholarly journals Systemic Corticosteroid Administration in Coronavirus Disease 2019 Outcomes: An Umbrella Meta-Analysis Incorporating Both Mild and Pulmonary Fibrosis–Manifested Severe Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Bin Cheng ◽  
Jinxiu Ma ◽  
Yani Yang ◽  
Tingting Shao ◽  
Binghao Zhao ◽  
...  
Keyword(s):  
Critically Ill ◽  
Meta Analysis ◽  
Severe Disease ◽  
Outcome Data ◽  
Sensitivity Analyses ◽  
Corticosteroid Administration ◽  
Random Effects Models ◽  
Hospital Stays ◽  
Meta Analyses ◽  
Negative Conversion

Background: Effective treatments for coronavirus disease 2019 (COVID-19) are urgently needed. The real role of corticosteroid use in COVID-19 has long been of interest and is disputable.Methods: We aimed to quantitatively reevaluate the efficacy of corticosteroids on COVID-19. Databases were searched for eligible meta-analyses/systematic reviews with available outcome data. For each association, we estimated the summary effect size with fixed- and random-effects models, 95% confidence intervals, and 95% prediction intervals. Heterogeneity, Egger’s test, evidence of small-study effects and excess significance bias, and subgroup analyses were rigorously evaluated.Results: Intended outcomes of 12 eligible studies were mortality, clinical improvement, hospitalization, mechanical ventilation (MV), adverse events (AEs), intensive care unit (ICU) stay, hospital stay, virus clearance time (VCT), and negative conversion. Corticosteroid administration was associated with a 27% risk reduction in MV [hazard ratio (HR): 0.73 (0.64–0.83)] and a 20% reduction in mortality of critically ill/severe COVID-19 patients [HR: 0.80 (0.65–0.98)]. Interestingly, shorter ICU stays and, conversely, potentially longer hospital stays, a longer VCT, and a longer time to negative conversion were associated with corticosteroid use. There was no significant impact of different corticosteroid doses on mortality. Only one study showed slightly excess significant bias. Caution should be applied given the weak nature of the evidence, and it has been confirmed by sensitivity analyses too.Conclusion: This umbrella study found benefits from corticosteroids on MV and especially the mortality of critically ill/severe patients with shorter ICU stays but prolonged hospital stays and VCT. The benefits and harms should be reevaluated and balanced before corticosteroids are cautiously prescribed in clinical practice.

scholarly journals Will Proton Pump Inhibitors Lead to a Higher Risk of COVID-19 Infection and Progression to Severe Disease? A Meta-analysis

2020 ◽  
Author(s):  
Cunye Yan ◽  
Yue Chen ◽  
Chenyu Sun ◽  
Mubashir Ayaz Ahmed ◽  
Chandur Bhan ◽  
...  
Keyword(s):  
Publication Bias ◽  
Proton Pump Inhibitors ◽  
Proton Pump ◽  
Mortality Risk ◽  
Fixed Effects ◽  
Secondary Infection ◽  
Meta Analysis ◽  
Severe Disease ◽  
Sensitivity Analyses ◽  
Increased Risk

AbstractBackgroundPrevious researches on the association between proton pump inhibitors (PPIs) use and the treatment and prevention of COVID-19 have generated inconsistent findings. Therefore, this Meta-analysis was conducted to clarify the outcome in patients who take PPIs.MethodsWe carried out a systematic search to identify potential studies until November 2020. Heterogeneity was assessed using the I-squared statistic. Odds ratios (ORs) with its 95% confidence intervals (CIs) were calculated by fixed-effects or random-effects models according to the heterogeneity. Sensitivity analyses and tests for publication bias were also performed.ResultsEight articles with more than 268,683 subjects were included. PPI use was not associated with increased or decreased risk of COVID-19 infection (OR:3.16, 95%CI = 0.74-13.43, P=0.12) or mortality risk of COVID-19 patients (OR=1.91, 95% CI=0.86-4.24, P=0.11). While it can add risk of severe disease (OR=1.54, 95% CI=1.20-1.99, P<0.001;) and secondary infection (OR=4.33, 95% CI=2.57-7.29). No publication bias was detected.ConclusionsPPI use is not associated with increased risk infection and may not change the mortality risk of COVID-19, but appeared to be associated with increased risk of progression to severe disease and secondary infection. However, more original studies to further clarify the relationship between PPI and COVID-19 are still urgently needed.

scholarly journals Treatment of toxic epidermal necrolysis with intravenous immunoglobulin: a series of three cases

2012 ◽  
Vol 87 (3) ◽  
pp. 477-481 ◽  
Author(s):  
Cristiane Comparin ◽  
Günter Hans Filho ◽  
Luiz Carlos Takita ◽  
Nayara de Castro Wiziack Costa ◽  
Roberta Ayres Ferreira do Nascimento ◽  
...  
Keyword(s):  
Toxic Epidermal Necrolysis ◽  
Intravenous Immunoglobulin ◽  
Fas Ligand ◽  
Immunoglobulin A ◽  
Death Receptor ◽  
Multidrug Therapy ◽  
Soluble Fas ◽  
Soluble Fas Ligand ◽  
Life Threatening ◽  
Cell Death Receptor

Stevens-Johnson's syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening dermatoses, that lead to keratinocyte apoptosis induced by interactions between Fas (cell death receptor) and soluble Fas-ligand, present in serum of Stevens-Johnson's syndrome / toxic epidermal necrolysis patients. Anti-Fas antibodies in intravenous immunoglobulin (IVIG) would block the apoptosis cascade. Three cases of toxic epidermal necrolysis occurred in one male and two female patients, after use of allopurinol, leprosy multidrug therapy concomitant with dipyrone, and diclofenac. The cases were treated with intravenous immunoglobulin 2-3 mg/kg and prednisone 20-50 mg/day. The interruption of new lesions outbreak and reepithelization were extremely fast after the use of intravenous immunoglobulin, without adverse effects. Controlled studies are needed to confirm the efficacy of intravenous immunoglobulin in Stevens-Johnson's syndrome / toxic epidermal necrolysis, but the results seem promising.

Indicated preventive interventions for anxiety in children and adolescents: a review and meta-analysis of school based programs

2019 ◽  
Author(s):  
Siobhan Hugh-Jones ◽  
Sophie Beckett ◽  
Pavan Mallikarjun
Keyword(s):  
Meta Analysis ◽  
Child And Adolescent ◽  
Sensitivity Analyses ◽  
Cochrane Library ◽  
Control Groups ◽  
Adolescent Anxiety ◽  
School Based ◽  
Intervention Intensity ◽  
Randomised Controlled ◽  
And Control

Schools are promising sites for the delivery of prevention and early intervention programs to reduce child and adolescent anxiety. It is unclear whether universal or targeted approaches are most effective. This review and meta-analysis examines the effectiveness of school-based indicated interventions and was registered with PROSPERO [CRD42018087628].MEDLINE, EMBASE, PsycINFO and the Cochrane Library were searched for randomised controlled trials comparing indicated school programs for child and adolescent anxiety to active or inactive control groups. Twenty original studies, with 2076 participants, met the inclusion criteria and 18 were suitable for meta-analysis. Sub-group and sensitivity analyses explored intervention intensity, delivery agent and control type. A small beneficial effect was found for indicated programs compared to controls on self-reported anxiety symptoms at post-test (g = -0.28, CI = -0.50, -0.05, k= 18). The small effect was maintained at 6 (g = -0.35, CI= -0.58, -0.13, k = 9) and 12 months (g = -0.24, CI = -0.48, 0.00, k = 4). Based on two studies, &gt;12 month effects were very small (g = -0.01, CI= -0.38, 0.36). No differences were found based on intervention intensity, delivery agent and control type. There was evidence of publication bias and a relatively high risk of contamination in studies. Findings support the value of school based indicated programs for child and adolescent anxiety. Effects at 12 months outperform many universal programs. High quality, randomised controlled and pragmatic trials are needed, with attention control groups and beyond 12 month diagnostic assessments are needed.

scholarly journals Hematologic, biochemical and immune biomarker abnormalities associated with severe illness and mortality in coronavirus disease 2019 (COVID-19): a meta-analysis

2020 ◽  
Vol 58 (7) ◽  
pp. 1021-1028 ◽  
Author(s):  
Brandon Michael Henry ◽  
Maria Helena Santos de Oliveira ◽  
Stefanie Benoit ◽  
Mario Plebani ◽  
Giuseppe Lippi
Keyword(s):  
Serum Ferritin ◽  
Weighted Mean Difference ◽  
Meta Analysis ◽  
Severe Disease ◽  
Severe Illness ◽  
China National Knowledge Infrastructure ◽  
Discriminative Ability ◽  
Laboratory Findings ◽  
Liver And Kidney ◽  
Wbc Count

AbstractBackgroundAs coronavirus disease 2019 (COVID-19) pandemic rages on, there is urgent need for identification of clinical and laboratory predictors for progression towards severe and fatal forms of this illness. In this study we aimed to evaluate the discriminative ability of hematologic, biochemical and immunologic biomarkers in patients with and without the severe or fatal forms of COVID-19.MethodsAn electronic search in Medline (PubMed interface), Scopus, Web of Science and China National Knowledge Infrastructure (CNKI) was performed, to identify studies reporting on laboratory abnormalities in patients with COVID-19. Studies were divided into two separate cohorts for analysis: severity (severe vs. non-severe and mortality, i.e. non-survivors vs. survivors). Data was pooled into a meta-analysis to estimate weighted mean difference (WMD) with 95% confidence interval (95% CI) for each laboratory parameter.ResultsA total number of 21 studies was included, totaling 3377 patients and 33 laboratory parameters. While 18 studies (n = 2984) compared laboratory findings between patients with severe and non-severe COVID-19, the other three (n = 393) compared survivors and non-survivors of the disease and were thus analyzed separately. Patients with severe and fatal disease had significantly increased white blood cell (WBC) count, and decreased lymphocyte and platelet counts compared to non-severe disease and survivors. Biomarkers of inflammation, cardiac and muscle injury, liver and kidney function and coagulation measures were also significantly elevated in patients with both severe and fatal COVID-19. Interleukins 6 (IL-6) and 10 (IL-10) and serum ferritin were strong discriminators for severe disease.ConclusionsSeveral biomarkers which may potentially aid in risk stratification models for predicting severe and fatal COVID-19 were identified. In hospitalized patients with respiratory distress, we recommend clinicians closely monitor WBC count, lymphocyte count, platelet count, IL-6 and serum ferritin as markers for potential progression to critical illness.

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