Identification of Macrophage Polarization-Related Genes as Biomarkers of Chronic Obstructive Pulmonary Disease Based on Bioinformatics Analyses

Objectives. Chronic obstructive pulmonary disease (COPD) is characterized by lung inflammation and remodeling. Macrophage polarization is associated with inflammation and tissue remodeling, as well as immunity. Therefore, this study attempts to investigate the diagnostic value and regulatory mechanism of macrophage polarization-related genes for COPD by bioinformatics analysis and to provide a new theoretical basis for experimental research. Methods. The raw gene expression profile dataset (GSE124180) was collected from the Gene Expression Omnibus (GEO) database. Next, a weighted gene coexpression network analysis (WGCNA) was conducted to screen macrophage polarization-related genes. The differentially expressed genes (DEGs) between the COPD and normal samples were generated using DESeq2 v3.11 and overlapped with the macrophage polarization-related genes. Moreover, functional annotations of overlapped genes were conducted by Database for Annotation, Visualization and Integrated Discovery (DAVID) Bioinformatics Resource. The immune-related genes were selected, and their correlation with the differential immune cells was analyzed by Pearson. Finally, receiver operating characteristic (ROC) curves were used to verify the diagnostic value of genes. Results. A total of 4922 coexpressed genes related to macrophage polarization were overlapped with the 203 DEGs between the COPD and normal samples, obtaining 25 genes related to COPD and macrophage polarization. GEM, S100B, and GZMA of them participated in the immune response, which were considered the candidate biomarkers. GEM and S100B were significantly correlated with marker genes of B cells which had a significant difference between the COPD and normal samples. Moreover, GEM was highly associated with the genes in the PI3K/Akt/GSK3β signaling pathway, regulation of actin cytoskeleton, and calcium signaling pathway based on a Pearson correlation analysis of the candidate genes and the genes in the B cell receptor signaling pathway. PPI network analysis also indicated that GEM might participate in the regulation of the PI3K/Akt/GSK3β signaling pathway. The ROC curve showed that GEM possessed an excellent accuracy in distinguishing COPD from normal samples. Conclusions. The data provide a transcriptome-based evidence that GEM is related to COPD and macrophage polarization likely contributes to COPD diagnosis. At the same time, it is hoped that in-depth functional mining can provide new ideas for exploring the COPD pathogenesis.

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Molecular mechanisms of phenotypic heterogeneity of chronic obstructive pulmonary disease: the role of JAK / STAT-, NFKB1-signaling pathway and inflammatory response molecules

Nauchno-prakticheskii zhurnal «Medicinskaia genetika» ◽

10.25557/2073-7998.2020.08.100-104 ◽

2020 ◽

pp. 100-104

Author(s):

Г.Ф. Корытина ◽

Ю.Г. Азнабаева ◽

М.Ю. Темнов ◽

Ш.Р. Зулькарнеев ◽

Л.З. Ахмадишина ◽

...

Keyword(s):

Gene Expression ◽

Chronic Obstructive Pulmonary Disease ◽

Inflammatory Response ◽

Pulmonary Disease ◽

Signaling Pathway ◽

Expression Profile ◽

Peripheral Blood ◽

Phenotypic Heterogeneity ◽

Chronic Obstructive ◽

Obstructive Pulmonary Disease

Хроническая обструктивная болезнь легких (ХОБЛ) - это многофакторное хроническое воспалительное заболевание респираторной системы. Одной из причин трудностей в идентификации маркеров ХОБЛ является фенотипическая гетерогенность. Цель - идентификация новых молекулярных маркеров патогенетических изменений, связанных с фенотипической гетерогеностью ХОБЛ на основе анализа профиля экспрессии генов вовлеченных в развитие иммунного ответа в мононуклеарных клетках периферической крови и анализа ассоциации полиморфных вариантов новых кандидатных генов с развитием ХОБЛ. Проведен сравнительный анализ профиля экспрессии панели 84 генов, кодирующих цитокины, хемокины в PBMC пациентов с различными фенотипами ХОБЛ: с частыми обострениями N=10 и редкими обострениями N=10 и контрольной группе N=10. Для анализа ассоциации использовали образцы ДНК больных ХОБЛ (N=601) и контроля (N=617), методом ПЦР в реальном времени проведен анализ 56 полиморфных локусов генов JAK/STAT-, NFKB1-сигнального путей, кодирующих белки, вовлеченные в реализацию реакций иммунного ответа и воспаления. Выявлены значимые изменения профиля экспрессии ряда генов в группе больных ХОБЛ с частыми обострениями. Впервые получены данные по вкладу полиморфных локусов генов JAK1, JAK3, STAT3, ICAM1, PECAM1, SAA1, NFKB1, IL17A, CCR2, CCR6, CCL8, CRP, CX3CL1, CXCR2, CXCR1, TNFRSF1A, IL20, IL19, в развитие данного заболевания. Выявлены специфические генетические маркеры развития фенотипа с частыми обострениями: CXCR2, TNFRSF1B, CCR6, TNF, IL1B, IL10, JAK3, PECAM1. Установлена ассоциация полиморфных вариантов генов TNFRSF1B, TNFRSF1A, CCL23, CXCR2, JAK1, NFKB1, PECAM1, ICAM1, STAT1, LTA, CD14, CXCL12, CCL20, ADIPOR1 и CX3CR1 с показателями функции внешнего дыхания. Определена взаимосвязь аллельных вариантов генов: IL17A, JAK1, JAK3, NFKB1, CCL5, CCL11, CCL17, CXCL8, TNFRSF1A, CX3CL1, CCL8, CCR6, CXCR2, IL19, IL20 с индексом курения. Chronic obstructive pulmonary disease (COPD) is a multifactorial heterogeneous chronic inflammatory disease of the respiratory system predominantly affecting the lower respiratory pathways and the lung parenchyma. One of the reason for difficulties in identifying of COPD markers is phenotypic heterogeneity. The goal of the study is the identification of new molecular markers of pathogenetic changes associated with phenotypic heterogeneity of COPD based on the analysis of the expression profile of genes involved in the development of the immune response in peripheral blood mononuclear cells and analysis of the association of polymorphic variants of new candidate genes with COPD. Methods: to identify differential gene expression in COPD we performed expression profiling of 84 cytokines and chemokines genes in peripheral blood samples from COPD (N=10 with frequent exacerbation phenotype, N=10 rare exacerbation phenotype) and N=10 smoking controls. RNA was isolated from PBMCs, and gene expression was assessed using RT2 Profiler PCR Arrays «Human Cytokines & Chemokines PCR Array»» (Qiagen, Valencia, CA, USA). 56 SNPs of JAK / STAT-, NFKB1-signaling pathway and inflammatory response molecules genes were genotyped by the real-time polymerase chain reaction (TaqMan assays) in a case-control study (601 COPD patients and 617 controls). Results. Significant changes were revealed in the expression profile of several genes in “frequent exacerbator» COPD phenotype. The results indicate a down-regulation of inflammatory molecules in “frequent exacerbator» COPD phenotype. For the first time, we indicated the contribution of JAK1, JAK3, STAT3, ICAM1, PECAM1, SAA1, NFKB1, IL17A, CCR2, CCR6, CCL8, CRP, CX3CL1, CXCR2, CXCR1, TNFRSF1A, IL20, IL19 genes polymorphisms to COPD. Specific genetic markers of “frequent exacerbator” COPD phenotype have been identified, which are modifiers of COPD progression, including polymorphic loci of the CXCR2, TNFRSF1B, CCR6, TNF, IL1B, IL10, JAK3, PECAM1 genes. A significant genotype-dependent variation of lung function parameters was observed for CXCR2, JAK1, NFKB1, PECAM1, ICAM1, STAT1, LTA, CD14, CXCL12, CCL20, ADIPOR1 and CX3CR1 genes. The relationship of IL17A, JAK1, JAK3, NFKB1, CCL5, CCL11, CCL17, CXCL8, TNFRSF1A, CX3CL1, CCL8, CCR6, CXCR2, IL19, IL20 genes with smoking pack-years was found.

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Diagnostic value of urea, creatinine and blood parameters in patients with pneumonia diagnosed with chronic obstructive pulmonary disease

F1000Research ◽

10.12688/f1000research.18538.1 ◽

2019 ◽

Vol 8 ◽

pp. 388 ◽

Cited By ~ 1

Author(s):

Seha Akduman

Keyword(s):

Chronic Obstructive Pulmonary Disease ◽

Pulmonary Disease ◽

White Blood Cells ◽

Diagnostic Value ◽

Blood Parameters ◽

Chronic Obstructive ◽

Characteristic Analysis ◽

Obstructive Pulmonary Disease ◽

Significant Difference ◽

First Time

Background: This study aimed to investigate the diagnostic value of urea, creatinine and other blood parameters in patients with pneumonia diagnosed with chronic obstructive pulmonary disease (COPD) for the first time. Methods: In this retrospective study, patients who had been diagnosed with COPD for the first time and were diagnosed with pneumonia were included. A total of 193 patients were divided into three groups as COPD + pneumonia (n=123), COPD (n=36) and pneumonia (n=34). Results: In total, 59 women (48.0%) and 64 men (52.0%) from the COPD + pneumonia group, 13 women (36.1%) and 23 men (63.9%) from the COPD group, 21 women (61.8%) and 13 men (38.2%) from the pneumonia group were assessed. The mean age of the COPD + pneumonia group was 69.58±13.62, 66.28±12.55 for the COPD group and 53.97±19.72 for the pneumonia group. The highest values of C-reactive protein (CRP), urea, creatinine, white blood cells (WBC), neutrophils, eosinophils and hemoglobin were the highest in COPD + pneumonia group. CRP levels were significantly different between COPD + pneumonia group (p<0.05). The parameters urea, WBC and neutrophils were significantly different between COPD + pneumonia group and pneumonia group (p<0.05). There was a statistically significant difference between COPD and pneumonia groups in terms of neutrophils and eosinophils values (p<0.05). According to the results of receiver operating characteristic analysis, the diagnostic value of the urea parameter in determining the COPD + pneumonia group was not statistically significant (p>0.05). On the other hand, the diagnostic value of CRP, WBC and neutrophils values were statistically significant (p<0.05). Conclusions: Elevation in WBC and neutrophil values in patients diagnosed with pneumonia have an important role in diagnosis of COPD.

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Epidemiology of Chronic Obstructive Pulmonary Disease (COPD) Comorbidities in Lithuanian National Database: A Cluster Analysis

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph19020970 ◽

2022 ◽

Vol 19 (2) ◽

pp. 970

Author(s):

Elena Jurevičienė ◽

Greta Burneikaitė ◽

Laimis Dambrauskas ◽

Vytautas Kasiulevičius ◽

Edita Kazėnaitė ◽

...

Keyword(s):

Lung Cancer ◽

Chronic Obstructive Pulmonary Disease ◽

Pulmonary Disease ◽

Kidney Diseases ◽

Screening Tools ◽

National Database ◽

Chronic Obstructive ◽

Obstructive Pulmonary Disease ◽

Significant Difference ◽

The Impact

Various comorbidities and multimorbidity frequently occur in chronic obstructive pulmonary disease (COPD), leading to the overload of health care systems and increased mortality. We aimed to assess the impact of COPD on the probability and clustering of comorbidities. The cross-sectional analysis of the nationwide Lithuanian database was performed based on the entries of the codes of chronic diseases. COPD was defined on the code J44.8 entry and six-month consumption of bronchodilators. Descriptive statistics and odds ratios (ORs) for associations and agglomerative hierarchical clustering were carried out. 321,297 patients aged 40–79 years were included; 4834 of them had COPD. A significantly higher prevalence of cardiovascular diseases (CVD), lung cancer, kidney diseases, and the association of COPD with six-fold higher odds of lung cancer (OR 6.66; p < 0.0001), a two-fold of heart failure (OR 2.61; p < 0.0001), and CVD (OR 1.83; p < 0.0001) was found. Six clusters in COPD males and five in females were pointed out, in patients without COPD—five and four clusters accordingly. The most prevalent cardiovascular cluster had no significant difference according to sex or COPD presence, but a different linkage of dyslipidemia was found. The study raises the need to elaborate adjusted multimorbidity case management and screening tools enabling better outcomes.

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Bioinformatic Analysis of ABCA1 Gene Expression in Smoking and Chronic Obstructive Pulmonary Disease

Membranes ◽

10.3390/membranes11090674 ◽

2021 ◽

Vol 11 (9) ◽

pp. 674

Author(s):

Stanislav Kotlyarov ◽

Anna Kotlyarova

Keyword(s):

Gene Expression ◽

Chronic Obstructive Pulmonary Disease ◽

Pulmonary Disease ◽

Alveolar Macrophages ◽

Plasma Membranes ◽

Bioinformatic Analysis ◽

Transport Processes ◽

Chronic Obstructive ◽

Obstructive Pulmonary Disease ◽

Abca1 Gene

Smoking is a key modifiable risk factor for developing the chronic obstructive pulmonary disease (COPD). When smoking, many processes, including the reverse transport of cholesterol mediated by the ATP binding cassette transporter A1 (ABCA1) protein are disrupted in the lungs. Changes in the cholesterol content in the lipid rafts of plasma membranes can modulate the function of transmembrane proteins localized in them. It is believed that this mechanism participates in increasing the inflammation in COPD. Methods: Bioinformatic analysis of datasets from Gene Expression Omnibus (GEO) was carried out. Gene expression data from datasets of alveolar macrophages and the epithelium of the respiratory tract in smokers and COPD patients compared with non-smokers were used for the analysis. To evaluate differentially expressed genes, bioinformatic analysis was performed in comparison groups using the limma package in R (v. 4.0.2), and the GEO2R and Phantasus tools (v. 1.11.0). Results: The conducted bioinformatic analysis showed changes in the expression of the ABCA1 gene associated with smoking. In the alveolar macrophages of smokers, the expression levels of ABCA1 were lower than in non-smokers. At the same time, in most of the airway epithelial datasets, gene expression did not show any difference between the groups of smokers and non-smokers. In addition, it was shown that the expression of ABCA1 in the epithelial cells of the trachea and large bronchi is higher than in small bronchi. Conclusions: The conducted bioinformatic analysis showed that smoking can influence the expression of the ABCA1 gene, thereby modulating lipid transport processes in macrophages, which are part of the mechanisms of inflammation development.

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Effect of Pharmacy Counseling on Readmissions in Patients with Acute Exacerbations of COPD: A Randomized Controlled Trial

Journal of Health Science and Medical Research ◽

10.31584/jhsmr.2021806 ◽

2021 ◽

Author(s):

Narachai Prasungriyo ◽

Nungruthai Sooksai

Keyword(s):

Chronic Obstructive Pulmonary Disease ◽

Pulmonary Disease ◽

Direct Costs ◽

Disease Assessment ◽

Chronic Obstructive ◽

P Value ◽

Intervention Period ◽

Obstructive Pulmonary Disease ◽

Significant Difference ◽

Acute Exacerbations

Objective: To investigate the effects of pharmacy counseling on clinical and economic outcomes in acute exacerbations of chronic obstructive pulmonary disease (AECOPD) patients.Material and Methods: The outcomes consisted of 28-day hospital readmissions related to AECOPD, direct costs, medication adherence calculated by proportion of days covered (PDC), and health-related quality of life (HRQoL) measured by chronic obstructive pulmonary disease assessment test (CAT). The data derived from the intervention group, for which pharmacy counseling was provided, was compared with that obtained from the control group provided with usual pharmaceutical care. The study also drew comparisons between the PDC and CAT scores of pre- and postintervention periods.Results: Forty-four patients (23 intervention and 21 control) were included in the analysis. There were no significant differences in the readmission rate (13% vs 19%, p-value>0.050), nor the number of readmitted patients (3 vs 3, p-value >0.050). A decrease in direct costs did not reach statistical significance (p-value>0.050). In addition, no difference between the PDC scores was found (96.67 vs 100.00, p-value>0.050). Intervention patients obtained significantly lower CAT scores than the control patients did (9 vs 19, p-value<0.050). Compared with the pre-intervention period, PDC scores were identical; however, CAT scores measured during the post-intervention period were significantly different.Conclusion: Pharmacy counseling for AECOPD patients could enhance HRQoL. Drug therapy and pulmonary rehabilitation may cause such improvement. Further work, which has adequate participants, is required to detect a significant difference in readmissions between the two groups.

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