Biology subjects

Obeidat, M.

Publications and source records attributed to Obeidat, M..

13 recordsLinked to original sources

bioRxiv2024

Acute sildenafil administration reduces susceptibility to induced atrial fibrillation in sheep

BackgroundSildenafil is a PDE5 inhibitor with a very good safety profile and animal models suggest it may be beneficial in the treatment of heart failure and ventricular fibrillation. Sildenafil has also been associated with a reduced incidence of atrial fibrillation (AF) in a retrospective observational study. We have therefore sought to determine whether sildenafil has a direct effect on atrial electrophysiology and resultant AF burden. MethodsInvasive electrophysiological studies were performed in 12 anaesthetised healthy adult female Welsh mountain sheep. Pacing protocols were performed in the right atrium before and after administration of an acute 10 mg intravenous bolus of sildenafil and the burden of AF assessed. ResultsSildenafil profoundly reduced the vulnerability to AF, decreasing AF duration (112.2 {+/-} 73.5 s vs. 3.3 {+/-} 1.4 s), the number of burst pacing inductions causing AF (90 % vs 70 %) and the complexity of AF. The antiarrhythmic effects of sildenafil were determined to be resultant of prolongation of both the atrial effective refractory period (146.9 {+/-} 7.2 ms vs 166.2 {+/-} 32.5 ms) and the atrial excitation wavelength (12.9 {+/-} 0.07 cm vs 15.0 {+/-} 0.07 cm) and resulted in a shallower restitution curve, reflected in a decreased magnitude of monophasic action potential alternans (0.09 {+/-} 0.001 mV vs 0.05 {+/-} 0.10 mV). ConclusionsIn the subjectively healthy atria of a highly translational model a strong antiarrhythmic effect upon acute sildenafil application was observed suggestive of a potential clinical benefit in AF.

physiology↗

bioRxiv2024

Biomarker Identification by Proteomic Analysis of Vitreous Humor and Plasma in Diabetic Retinopathy

ImportanceIdentify detectable plasma and/or vitreous signals to potentially predict diabetic retinopathy (DR) progression for earlier disease intervention. ObjectiveTo determine the mediators and potential disease progression biomarkers of DR in vitreous humor (VH) and plasma samples using the SomaScan proteome profiling platform. DesignDifferential expression analysis was conducted on VH and plasma samples using the SomaScan Assay. SettingA non-interventional study conducted to collect and analyze VH and plasma samples from patients with diabetic retinopathy. ParticipantsSamples from DR (60 nonproliferative diabetic retinopathy/NPDR, 60 proliferative diabetic retinopathy/PDR) and 60 control patients were collected. Main outcomes and MeasuresDifferentially expressed proteins between disease and control groups were identified. Pathway enrichment analysis was conducted to identify significantly perturbed pathways in DR. Finally, a random forest model was used to identify predictive biomarkers of disease progression. ResultsSomaScan v3 is a pooled aptamer hybridization assay using 5080 SOMAmers to probe over 4100 proteoforms in VH and plasma samples from 3 groups (control, NPDR, and PDR). The most profound protein content change was observed in the VH samples of PDR patients, while minimal changes were measured in plasma samples, highlighting the regionality of PDR pathogenesis. Many key molecules and molecular pathways such as VEGF-A, erythropoietin, and inflammation-associated proteins implicated in DR were significantly affected in the VH of PDR patients. In addition to the classic pathways (hypoxia, immune response, mTORC1 signaling) known to be involved in PDR, novel signaling pathways, including HEME metabolism and adipogenesis, were identified in VH samples. Application of a machine learning algorithm identified a panel of plasma PDR predictive biomarkers and revealed SCARA5 as the top one based on the largest average Gini decrease in the model. ConclusionOur study identified profound alteration of protein expression and molecular pathways in the VH of PDR patients, supporting the key role of local pathogenic changes in DR progression compared to systemic factors. Although the systemic changes related to DR were small, a few disease progression predictive candidate biomarkers (SCARA5, PTK7, FAM3Band FAM3D) were identified, prompting further investigation. Key PointsQuestion: Are plasma/ vitreous humor (VH) proteins predictive of diabetic retinopathy (DR) progression? Findings: This study identifies substantial protein changes in the VH of proliferative diabetic retinopathy (PDR) patients, while early nonproliferative DR (NPDR) patients show minimal change. We identify multiple proteins linked to angiogenesis, inflammation, immune cells (microglia/macrophage/neutrophil), and leukostasis associated with PDR and reveal a potential plasma panel of disease progression (from NPDR to PDR) biomarkers (SCARA5, PTK7, FAM3B, FAM3D). Meaning: Identified disease progression predictive biomarkers permits potential development of prognostic tools to identify individuals most at risk for PDR progression and offering reduced disease burden by earlier intervention.

physiology↗

bioRxiv2019

The protective effect of club cell secretory protein (CC-16) on COPD risk and progression: a Mendelian randomisation study

BackgroundThere are currently no robust biomarkers of chronic obstructive pulmonary disease (COPD) risk or progression. Club cell secretory protein-16 (CC-16) is associated with the clinical expression of COPD. We aimed to determine if there is a causal effect of serum CC-16 level on COPD risk and/or progression using Mendelian randomisation (MR) analysis. MethodsWe performed a genome-wide association meta-analysis for serum CC-16 in two COPD cohorts (Lung Health Study [LHS], n=3,850 and ECLIPSE, n=1,702). We then used the CC-16-associated single-nucleotide polymorphisms (SNPs) in MR analysis to estimate the causal effect of serum CC-16 on COPD risk (International COPD Genetics Consortium/UK-Biobank dataset; n=35,735 cases, n=222,076 controls) and progression (change in forced expiratory volume in 1 s [FEV1] in LHS and ECLIPSE). We also determined the associations between SNPs associated with CC-16 and gene expression using n=1,111 lung tissue samples from the Lung eQTL Study. ResultsWe identified 7 SNPs independently associated (p<5x10-8) with serum CC-16 levels; 6 of these were novel. MR analysis suggested a protective causal effect of increased serum CC-16 on COPD risk (p=0.008) and progression (LHS only, p=0.02). Five of the SNPs were also associated with gene expression in lung tissue, including that of the CC-16-encoding gene SCGB1A1 (false discovery rate<0.1). ConclusionWe have identified several novel genetic variants associated with serum CC-16 level in COPD cohorts. These genetic associations suggest a potential causal effect of serum CC-16 on COPD risk and progression. Further investigation of CC-16 as a biomarker or therapeutic target in COPD is warranted. KEY MESSAGESWhat is the key question? Can genetics help uncover a causal effect of serum CC-16 level on COPD risk and/or progression? What is the bottom line? There is a protective effect of genetically-increased serum CC-16 on both COPD risk and progression (as measured by change in FEV1 over time), which may be due to increased expression of the CC-16-encoding gene SCGB1A1 in the lung. Why read on? This is the first study to demonstrate a possible causal effect of serum CC-16 in people with COPD, and highlights the potential for CC-16 as a biomarker or therapeutic target.

genomics↗

bioRxiv2019

The Topology of Mutated Driver Pathways

Much progress has been made, and continues to be made, towards identifying candidate mutated driver pathways in cancer. However, no systematic approach to understanding how candidate pathways relate to each other for a given cancer (such as Acute myeloid leukemia), and how one type of cancer may be similar or different from another with regard to their respective pathways (Acute myeloid leukemia vs. Glioblastoma multiforme for instance), has emerged thus far. Our work attempts to contribute to the understanding of space of pathways through a novel topological framework. We illustrate our approach, using mutation data (obtained from TCGA) of two types of tumors: Acute myeloid leukemia (AML) and Glioblastoma multiforme (GBM). We find that the space of pathways for AML is homotopy equivalent to a sphere, while that of GBM is equivalent to a genus-2 surface. We hope to trigger new types of questions (i.e., allow for novel kinds of hypotheses) towards a more comprehensive grasp of cancer.

bioinformatics↗

bioRxiv2019

Genome-wide association study of susceptibility to idiopathic pulmonary fibrosis

RationaleIdiopathic pulmonary fibrosis (IPF) is a complex lung disease characterised by scarring of the lung that is believed to result from an atypical response to injury of the epithelium. The mechanisms by which this arises are poorly understood and it is likely that multiple pathways are involved. The strongest genetic association with IPF is a variant in the promoter of MUC5B where each copy of the risk allele confers a five-fold risk of disease. However, genome-wide association studies have reported additional signals of association implicating multiple pathways including host defence, telomere maintenance, signalling and cell-cell adhesion.\n\nObjectivesTo improve our understanding of mechanisms that increase IPF susceptibility by identifying previously unreported genetic associations.\n\nMethods and measurementsWe performed the largest genome-wide association study undertaken for IPF susceptibility with a discovery stage comprising up to 2,668 IPF cases and 8,591 controls with replication in an additional 1,467 IPF cases and 11,874 controls. Polygenic risk scores were used to assess the collective effect of variants not reported as associated with IPF.\n\nMain resultsWe identified and replicated three new genome-wide significant (P<5x10-8) signals of association with IPF susceptibility (near KIF15, MAD1L1 and DEPTOR) and confirm associations at 11 previously reported loci. Polygenic risk score analyses showed that the combined effect of many thousands of as-yet unreported IPF risk variants contribute to IPF susceptibility.\n\nConclusionsNovel association signals support the importance of mTOR signalling in lung fibrosis and suggest a possible role of mitotic spindle-assembly genes in IPF susceptibility.

genomics↗

bioRxiv2019

Immune-mediated genetic pathways resulting in pulmonary function impairment increase lung cancer susceptibility

Impaired lung function is often caused by cigarette smoking, making it challenging to disentangle its role in lung cancer susceptibility. Investigation of the shared genetic basis of these phenotypes in the UK Biobank and International Lung Cancer Consortium (29,266 cases, 56,450 controls) shows that lung cancer is genetically correlated with reduced forced expiratory volume in one second (FEV1: rg=0.098, p=2.3x10-8) and the ratio of FEV1 to forced vital capacity (FEV1/FVC: rg=0.137, p=2.0x10-12). Mendelian randomization analyses demonstrate that reduced FEV1 increases squamous cell carcinoma risk (odds ratio (OR)=1.51, 95% confidence intervals: 1.21-1.88), while reduced FEV1/FVC increases the risk of adenocarcinoma (OR=1.17, 1.01-1.35) and lung cancer in never smokers (OR=1.56, 1.05-2.30). These findings support a causal role of pulmonary impairment in lung cancer etiology. Integrative analyses reveal that pulmonary function instruments, including 73 novel variants, influence lung tissue gene expression and implicate immune-related pathways in mediating the observed effects on lung carcinogenesis.

genetics↗

bioRxiv2019

Widespread Sexual Dimorphism in the Transcriptome of Human Airway Epithelium in Response to Smoking

Epidemiological studies have shown that female smokers are at higher risk of chronic obstructive pulmonary disease (COPD). Female patients have worse symptoms and health status and increased risk of exacerbations. We determined the differences in the transcriptome of the airway epithelium between males and females at baseline and in response to smoking. We processed public gene expression data of human airway epithelium into a discovery cohort of 211 subjects (never smokers n=68; current smokers n=143) and two replication cohorts of 104 subjects (21 never, 52 current, and 31 former smokers) and 238 subjects (99 current and 139 former smokers. We analyzed gene differential expression with smoking status, sex, and smoking-by-sex interaction and used network approaches for modules level analyses. We identified and replicated two differentially expressed modules between the sexes in response to smoking with genes located throughout the autosomes and not restricted to sex chromosomes. The two modules were enriched in autophagy (up-regulated in female smokers) and response to virus and type 1 interferon signaling pathways which were down-regulated in female smokers compared to males. The results offer insights into the molecular mechanisms of the sexually dimorphic COPD risk and presentation potentially enabling a precision medicine approach to COPD.

genomics↗

bioRxiv2019

SNPs associated with HHIP expression have differential effects on lung function in males and females

Adult lung function is highly heritable and 279 genetic loci were recently reported as associated with spirometry-based measures of lung function. Though lung development and function differ between males and females throughout life, there has been no genome-wide study to identify genetic variants with differential effects on lung function in males and females. Here, we present the first genome-wide genotype-by-sex interaction study on four lung function traits in 303,612 participants from the UK Biobank. We detected five SNPs showing genome-wide significant (P<5 x 10-8) interactions with sex on lung function, as well as 21 suggestively significant interactions (P<1 x 10-6). The strongest sex interaction signal came from rs7697189 at 4:145436894 on forced expiratory volume in 1 second (FEV1) (P = 3.15 x 10-15), and was replicated (P = 0.016) in 75,696 individuals in the SpiroMeta consortium. Sex-stratified analyses demonstrated that the minor (C) allele of rs7697189 increased lung function to a greater extent in males than females (untransformed FEV1 {beta} = 0.028 [SE 0.0022] litres in males vs {beta} = 0.009 [SE 0.0014] litres in females), and this effect was not accounted for by differential effects on height, smoking or age at puberty. This SNP resides upstream of the gene encoding hedgehog-interacting protein (HHIP) and has previously been reported for association with lung function and HHIP expression in lung tissue. In our analyses, while HHIP expression in lung tissue was significantly different between the sexes with females having higher expression (most significant probeset P=6.90 x 10-6) after adjusting for age and smoking, rs7697189 did not demonstrate sex differential effects on expression. Establishing the mechanism by which HHIP SNPs have different effects on lung function in males and females will be important for our understanding of lung health and diseases, such as chronic obstructive pulmonary disease (COPD), in both sexes.

genetics↗

bioRxiv2018

Expanded genetic landscape of chronic obstructive pulmonary disease reveals heterogeneous cell type and phenotype associations

Chronic obstructive pulmonary disease (COPD) is the leading cause of respiratory mortality worldwide. Genetic risk loci provide novel insights into disease pathogenesis. To broaden COPD genetic risk loci discovery and identify cell type and phenotype associations we performed a genome-wide association study in 35,735 cases and 222,076 controls from the UK Biobank and additional studies from the International COPD Genetics Consortium. We identified 82 loci with P value < 5x10-8; 47 were previously described in association with either COPD or population-based lung function. Of the remaining 35 novel loci, 13 were associated with lung function in 79,055 individuals from the SpiroMeta consortium. Using gene expression and regulation data, we identified enrichment for loci in lung tissue, smooth muscle and alveolar type II cells. We found 9 shared genomic regions between COPD and asthma and 5 between COPD and pulmonary fibrosis. COPD genetic risk loci clustered into groups of quantitative imaging features and comorbidity associations. Our analyses provide further support to the genetic susceptibility and heterogeneity of COPD.

genetics↗

bioRxiv2018

New genetic signals for lung function highlight pathways and pleiotropy, and chronic obstructive pulmonary disease associations across multiple ancestries

Reduced lung function predicts mortality and is key to the diagnosis of COPD. In a genome-wide association study in 400,102 individuals of European ancestry, we define 279 lung function signals, one-half of which are new. In combination these variants strongly predict COPD in deeply-phenotyped patient populations. Furthermore, the combined effect of these variants showed generalisability across smokers and never-smokers, and across ancestral groups. We highlight biological pathways, known and potential drug targets for COPD and, in phenome-wide association studies, autoimmune-related and other pleiotropic effects of lung function associated variants. This new genetic evidence has potential to improve future preventive and therapeutic strategies for COPD.

genomics↗

bioRxiv2017

Multiethnic Meta-analysis Identifies New Loci for Pulmonary Function

Nearly 100 loci have been identified for pulmonary function, almost exclusively in studies of European ancestry populations. We extend previous research by meta-analyzing genome-wide association studies of 1000 Genomes imputed variants in relation to pulmonary function in a multiethnic population of 90,715 individuals of European (N=60,552), African (N=8,429), Asian (N=9,959), and Hispanic/Latino (N=11,775) ethnicities. We identified over 50 novel loci at genome-wide significance in ancestry-specific and/or multiethnic meta-analyses. Recent fine mapping methods incorporating functional annotation, gene expression, and/or differences in linkage disequilibrium between ethnicities identified potential causal variants and genes at known and newly identified loci. Sixteen of the novel genes encode proteins with predicted or established drug targets, including KCNK2 and CDK12.

genetics↗

bioRxiv2017

Leveraging lung tissue transcriptome to uncover candidate causal genes in COPD genetic associations

We collated 129 non-overlapping risk loci for chronic obstructive pulmonary disease (COPD) from the GWAS literature. Using recent and complementary integrative genomics approaches, combining GWAS and lung eQTL results, we identified 12 novel COPD loci and corresponding causal genes. In addition, we mapped candidate causal genes for 60 out of the 129 GWAS-nominated loci as well as for four sub-genome-wide significant COPD risk loci derived from the largest GWAS on COPD. Mapping causal genes in lung tissue represents an important contribution on the genetics of COPD, enriches our biological interpretation of GWAS findings, and brings us closer to clinical translation of genetic associations.

genomics↗

bioRxiv2017

Meta-analysis of exome array data identifies six novel genetic loci for lung function

Over 90 regions of the genome have been associated with lung function to date, many of which have also been implicated in chronic obstructive pulmonary disease (COPD). We carried out meta-analyses of exome array data and three lung function measures: forced expiratory volume in one second (FEV1), forced vital capacity (FVC) and the ratio of FEV1 to FVC (FEV1/FVC). These analyses by the SpiroMeta and CHARGE consortia included 60,749 individuals of European ancestry from 23 studies, and 7,721 individuals of African Ancestry from 5 studies in the discovery stage, with follow-up in up to 111,556 independent individuals. We identified significant (P<2{middle dot}8x10-7) associations with six SNPs: a nonsynonymous variant in RPAP1, which is predicted to be damaging, three intronic SNPs (SEC24C, CASC17 and UQCC1) and two intergenic SNPs near to LY86 and FGF10. eQTL analyses found evidence for regulation of gene expression at three signals and implicated several genes including TYRO3 and PLAU. Further interrogation of these loci could provide greater understanding of the determinants of lung function and pulmonary disease.

genetics↗