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In silico analysis of the molecular regulatory networks in peripheral arterial occlusive disease.

ABSTRACT: BACKGROUND:Peripheral arterial occlusive disease (PAOD) is a global public health concern that decreases the quality of life of the patients and can lead to disabilities and death. The aim of this study was to identify the genes and pathways associated with PAOD pathogenesis, and the potential therapeutic targets. METHODS:Differentially expressed genes (DEGs) and miRNAs related to PAOD were extracted from the GSE57691 dataset and through text mining. Additionally, bioinformatics analysis was applied to explore gene ontology, pathways and protein-protein interaction of those DEGs. The potential miRNAs targeting the DEGs and the transcription factors (TFs) regulating miRNAs were predicted by multiple different databases. RESULTS:A total of 59 DEGs were identified, which were significantly enriched in the inflammatory response, immune response, chemokine-mediated signaling pathway and JAK-STAT signaling pathway. Thirteen genes including IL6, CXCL12, IL1B, and STAT3 were hub genes in protein-protein interaction network. In addition, 513 miRNA-target gene pairs were identified, of which CXCL12 and PTPN11 were the potential targets of miRNA-143, and IL1B of miRNA-21. STAT3 was differentially expressed and regulated 27 potential target miRNAs including miRNA-143 and miRNA-21 in TF-miRNA regulatory network. CONCLUSION:In summary, inflammation, immune response and STAT3-mediated miRNA-target genes axis play an important role in PAOD development and progression.

SUBMITTER: Guan X

PROVIDER: S-EPMC7250035 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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In silico analysis of the molecular regulatory networks in peripheral arterial occlusive disease.

Guan Xuwen X Yang Xiaoyan X Wang Chunming C Bi Renbing R

Medicine 20200501 21

<h4>Background</h4>Peripheral arterial occlusive disease (PAOD) is a global public health concern that decreases the quality of life of the patients and can lead to disabilities and death. The aim of this study was to identify the genes and pathways associated with PAOD pathogenesis, and the potential therapeutic targets.<h4>Methods</h4>Differentially expressed genes (DEGs) and miRNAs related to PAOD were extracted from the GSE57691 dataset and through text mining. Additionally, bioinformatics a ...[more]

PMID: 32481342

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Project description:BackgroundThis study aimed to determine the prevalence of genetic and environmental vascular risk factors in non diabetic patients with premature peripheral arterial disease, either peripheral arterial occlusive disease or thromboangiitis obliterans, the two main entities of peripheral arterial disease, and to established whether some of them are specifically associated with one or another of the premature peripheral arterial disease subgroups.Methods and resultsThis study included 113 non diabetic patients with premature peripheral arterial disease (diagnosis <45-year old) presenting either a peripheral arterial occlusive disease (N?=?64) or a thromboangiitis obliterans (N?=?49), and 241 controls matched for age and gender. Both patient groups demonstrated common traits including cigarette smoking, low physical activity, decreased levels of HDL-cholesterol, apolipoprotein A-I, pyridoxal 5'-phosphate (active form of B6 vitamin) and zinc. Premature peripheral arterial occlusive disease was characterized by the presence of a family history of peripheral arterial and carotid artery diseases (OR 2.3 and 5.8 respectively, 95% CI), high lipoprotein (a) levels above 300 mg/L (OR 2.3, 95% CI), the presence of the factor V Leiden (OR 5.1, 95% CI) and the glycoprotein Ia(807T,837T,873A) allele (OR 2.3, 95% CI). In thromboangiitis obliterans group, more patients were regular consumers of cannabis (OR 3.5, 95% CI) and higher levels in plasma copper has been shown (OR 6.5, 95% CI).ConclusionsAccording to our results from a non exhaustive list of study parameters, we might hypothesize for 1) a genetic basis for premature peripheral arterial occlusive disease development and 2) the prevalence of environmental factors in the development of thromboangiitis obliterans (tobacco and cannabis). Moreover, for the first time, we demonstrated that the 807T/837T/873A allele of platelet glycoprotein Ia may confer an additional risk for development of peripheral atherosclerosis in premature peripheral arterial occlusive disease.

Project description:BackgroundPeripheral arterial disease (PAD), a major manifestation of atherosclerosis, is associated with significant cardiovascular morbidity, limb loss and death. However, mechanisms underlying the genesis and progression of the disease are far from clear. Genome-wide gene expression profiling of clinical samples may represent an effective approach to gain relevant information.ResultsAfter histological classification, a total of 30 femoral artery samples, including 11 intermediate lesions, 14 advanced lesions and 5 normal femoral arteries, were profiled using Affymetrix microarray platform. Following real-time RT-PCR validation, different algorithms of gene selection and clustering were applied to identify differentially expressed genes. Under a stringent cutoff, i.e., a false discovery rate (FDR) <0.5%, we found 366 genes were differentially regulated in intermediate lesions and 447 in advanced lesions. Of these, 116 genes were overlapped between intermediate and advanced lesions, including 68 up-regulated genes and 48 down-regulated ones. In these differentially regulated genes, immune/inflammatory genes were significantly up-regulated in different stages of PAD, (85/230 in intermediate lesions, 37/172 in advanced lesions). Through literature mining and pathway analysis using different databases such as Gene Ontology (GO), and the Kyoto Encyclopedia of Gene and Genomics (KEGG), genes involved in immune/inflammatory responses were significantly enriched in up-regulated genes at different stages of PAD(p < 0.05), revealing a significant correlation between immune/inflammatory responses and disease progression. Moreover, immune-related pathways such as Toll-like receptor signaling and natural killer cell mediated cytotoxicity were particularly enriched in intermediate and advanced lesions (P < 0.05), highlighting their pathogenic significance during disease progression.ConclusionLines of evidence revealed in this study not only support previous hypotheses, primarily based on studies of animal models and other types of arterial disease, that inflammatory responses may influence the development of PAD, but also permit the recognition of a wide spectrum of immune/inflammatory genes that can serve as signatures for disease progression in PAD. Further studies of these signature molecules may eventually allow us to develop more sophisticated protocols for pharmaceutical interventions.

Project description:ObjectivesPeripheral arterial occlusive disease (PAOD) and periodontitis are common chronic diseases, which together affect almost 1 billion people worldwide. There is growing evidence suggesting a relationship between chronic inflammatory conditions such as periodontitis and PAOD. This study aims to determine an association between both entities using high quality research data and multiple phenotypes derived from an epidemiological cohort study.DesignThis population-based cross-sectional cohort study included data from 3271 participants aged between 45 and 74 years enrolled in the Hamburg City Health Study (NCT03934957).Material & methodsAn ankle-brachial-index below 0.9, color-coded ultrasound of the lower extremity arteries, and survey data was used to identify participants with either asymptomatic or symptomatic PAOD. Periodontitis data was collected at six sites per tooth and included the probing depth, gingival recession, clinical attachment loss, and bleeding on probing index. Multivariate analyses using logistic regression models were adjusted for variables including age, sex, smoking, education, diabetes, and hypertension.ResultsThe baseline characteristics differed widely between participants neither affected by periodontitis nor PAOD vs. the group where both PAOD and severe periodontitis were identified. A higher rate of males, higher age, lower education level, smoking, diabetes, and cardiovascular disease was observed in the group affected by both diseases. After adjusting, presence of severe periodontitis (odds ratio 1.265; 97.5% CI 1.006-1.591; p = 0.045) was independently associated with PAOD.ConclusionIn this cross-sectional analysis of a prospective cohort study, an independent association between periodontitis and PAOD was revealed. The results of the current study emphasize a potential for preventive medicine in an extremely sensitive target population. Future studies should determine the underlying factors modifying the relationship between both diseases.

Project description:ObjectivesPatients with peripheral arterial occlusive disease (PAOD) are at risk of worsening limb symptoms, major adverse cardiovascular events and exhibit an impaired life expectancy. There is a lack of evidence on the extent of pharmacological secondary prevention in PAOD patients. This study assesses treatment patterns of antithrombotic agents in symptomatic PAOD patients.MethodsThis is a retrospective cohort study using data from the second largest insurance fund in Germany, BARMER. We included symptomatic PAOD patients undergoing in-hospital treatment with an index admission between 1 January 2010 and 31 December 2017. Outcomes were proportions of single antiplatelets (SAPT), dual antiplatelets (DAPT), vitamin-K antagonists (VKA), or direct oral anticoagulants (DOAC) in the 12 months prior and 6 months after the index hospitalization. Non-parametric cumulative incidence for competing risks was estimated to account for censoring and death after discharge from hospital stay. Patient flows were visualised by alluvial diagrams. All analyses were stratified by intermittent claudication (IC) and chronic limb-threatening ischaemia (CLTI). The protocol was registered to ClinicalTrials.gov (NCT03909022).ResultsA total of 80,426 unique patient encounters were identified. Mean age was 72.7 (46.3% female). Amongst all patients, 25.6% were on SAPT, 4.1% on DAPT, 9.1% on VKA, 3.9% on DOAC, 3.9% on both antiplatelets and oral anticoagulation, and 53.3% without any antithrombotic therapy during the 12 months before index stay. The estimated cumulative incidence was 37.9% SAPT, 14.8% DAPT, 7.5% VKA, 4.3% DOAC, 7.4% both, and 28.1% without any antithrombotic therapy during the 6 months after index stay. The considerable increases in antiplatelet therapy were mainly driven by the group of patients without antithrombotics before index stay. As compared with IC, patients who suffered from CLTI received less often antiplatelets but more often anticoagulants both before and after index stay.ConclusionsUtilisation rates of antithrombotic therapy increased considerably after in-hospital treatment for PAOD. Yet, remarkably high rates of symptomatic patients without any blood-thinning therapy constitute a major concern with respect to adequate secondary prevention of PAOD patients.

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In silico analysis of the molecular regulatory networks in peripheral arterial occlusive disease.

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In silico analysis of the molecular regulatory networks in peripheral arterial occlusive disease.

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