Identification of hub genes and key pathways in the emphysema phenotype of COPD

Zuo, Qiunan; Wang, Youyu; Yang, Deqing; Guo, Shujin; Li, Xiaohui; Dong, Jiajia; Wan, Chun; Shen, Yongchun; Wen, Fuqiang

doi:10.18632/aging.202432

Cited by 13 publications

(18 citation statements)

References 42 publications

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“…In this study, RNA-seq was used to obtain DEGs in the blood of different stages of COPD. Combined with bioinformatics analysis, multiple signaling pathways were found to participate in the pathogenesis of AECOPD, which is consistent with previous studies [ 9 , 12 – 14 ]. Importantly, we demonstrated, for the first time, that the WNT/β-catenin signaling pathway is decreased in patients with AECOPD.…”

Section: Discussionsupporting

confidence: 90%

Transcriptomic analysis and validation reveal the pathogenesis and a novel biomarker of acute exacerbation of chronic obstructive pulmonary disease

Wang

Zhong

et al. 2022

Respir Res

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Background Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is the main factor that leads to the deterioration of the disease. Currently, the diagnosis of AECOPD mainly relies on clinical manifestations, good predictors or biomarkers are lacking. We aim to reveal specific biomarkers and potential pathogenesis of AECOPD and provide a research basis for the diagnosis and treatment. Methods Four patients with AECOPD, four patients with stable COPD, and five control subjects were enrolled for RNA sequencing and KEGG analysis. The mRNA level of target genes was verified by quantitative real-time PCR (qPCR) with an expanded sample size (30 patients with AECOPD, 27 patients with stable COPD, and 35 control subjects). ELISA and immunofluorescence were used to identify the target proteins. Furthermore, the expression and function of WNT/β-catenin signaling pathway were assessed in animal models of COPD. Results RNA sequencing showed that 54 genes were up-regulated and 111 genes were down-regulated in the AECOPD. Differentially expressed genes were mainly enriched in WNT signaling pathway, et al. QPCR revealed that multi-genes of the WNT/β-catenin signaling were significantly down-regulated in AECOPD (P < 0.05), and β-catenin protein was significantly decreased in plasma of AECOPD and stable COPD (P < 0.01), while phosphorylated β-catenin was significantly up-regulated in peripheral blood mononuclear cells of AECOPD (P < 0.05). Similarly, WNT ligands, WNT receptors, and downstream signaling molecules were down-regulated, with an increased phosphorylated β-catenin protein in animal models of COPD. Activation of WNT/β-catenin signaling pathway by lithium chloride reduced the expression of phosphorylated β-catenin and ameliorated the COPD-like airway inflammation in mice. Conclusion WNT/β-catenin signaling pathway is down-regulated in AECOPD patients and in animal models of COPD. Increased expression of phosphorylated β-catenin in the blood might be a potential biomarker of AECOPD. Activation of WNT/β-catenin pathway may also represent a therapeutic target for AECOPD.

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Section: Discussionsupporting

confidence: 90%

Transcriptomic analysis and validation reveal the pathogenesis and a novel biomarker of acute exacerbation of chronic obstructive pulmonary disease

Wang

Zhong

et al. 2022

Respir Res

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“…A growing but limited number of studies have examined emphysema biomarkers and biological pathways. The extracellular matrix (ECM), NF-κB, transforming growth factor beta (TGF-ß), B cell antigen receptor (BCR), and oxidative phosphorylation pathways are among the most reported in these studies (10, 45, 46). However, although researched from various sources, including peripheral blood, lung tissue, and sputum, most identified pathways and biomarkers originate from studying a single ‘omics modality at a time (22, 27, 47).…”

Section: Discussionmentioning

confidence: 99%

Blood-Based Transcriptomic and Proteomic Biomarkers of Emphysema

Suryadevara

Gregory

et al. 2022

Preprint

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Rationale: Emphysema is a key component of COPD with important prognostic implications. Identifying blood-based biomarkers of emphysema will facilitate early diagnosis and possible development of targeted therapies. Objectives: Discover blood transcriptomic and proteomic biomarkers for chest computed tomography-quantified emphysema in smokers and develop predictive biomarker panels. Methods: Emphysema blood biomarker discovery was performed using differential gene expression, alternative splicing, and protein association analyses in a training set of 2,370 COPDGene participants with available whole blood RNA sequencing, plasma SomaScan proteomics, and clinical data. Validation was conducted in a testing set of 1,016 COPDGene subjects. Since body mass index (BMI) and emphysema often co-occur, we performed a mediation analysis to quantify the effect of BMI on gene and protein associations with emphysema. Predictive models were also developed using elastic net to predict quantitative emphysema from cell blood count, RNA sequencing, and proteomic biomarkers. Model accuracy was assessed by area under the receiver-operator-characteristic-curves (AUROC) for subjects stratified into tertiles of emphysema severity. Measurements and Main Results: 4,913 genes, 1,478 isoforms, 386 exons, and 881 proteins were significantly associated with emphysema (FDR 10%). 75% and 77% of genes and proteins, respectively, were mediated by BMI. The significantly enriched biological pathways were involved in inflammation and cell differentiation, differing between the most and least BMI-mediated genes. The cell blood count plus protein model achieved the highest performance with an AUROC of 0.89. Conclusions: Blood transcriptome and proteome-wide analyses reveal key biological pathways of emphysema and enhance the prediction of emphysema.

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“…Consistent with previous research, CD19 and POU2AF1 were significantly upregulated and may be key genes in emphysema related to COPD. 14 , 19 , 33 …”

Section: Discussionmentioning

confidence: 99%

“… 13 A recent study found that some B-cell-related genes, including CD19 and POU2AF1 were identified as the hub genes involved in the emphysema phenotype of COPD patients. 14 CD19 is expressed from the earliest stages of B cell development until plasma cell terminal differentiation when its expression is lost. 15 POU2AF1 is a transcriptional coactivator and is essential for the response of B-cells to antigens and required for the formation of germinal centers.…”

Section: Introductionmentioning

confidence: 99%

CD19 and POU2AF1 are Potential Immune-Related Biomarkers Involved in the Emphysema of COPD: On Multiple Microarray Analysis

Zhang¹,

Ye²,

Sun³

et al. 2022

JIR

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Purpose Emphysema is the main cause of the progression of chronic obstructive pulmonary disease (COPD). This study aimed to identify the key genes involved in COPD-related emphysema. Patients and Methods GSE76925 was downloaded from Gene Expression Omnibus database. Protein–protein interaction networks of differentially expressed genes (DEGs) between control and COPD groups were constructed to identify hub genes using Cytoscape. Diagnostic performance of hub genes was evaluated using receiver operating characteristic analysis. Correlation analysis was performed to identify the key genes by analyzing the relationship between the hub genes and lung function and computed tomography (CT) indexes of emphysema. COPD patients were then divided into two groups based on the median expression of key genes and DEGs between these two groups were identified. Enrichment analysis of DEGs and correlation analysis between key genes and the infiltration of the immune cells were also analyzed. Finally, the role of key genes was evaluated in a lung tissues dataset (GSE47460) and a blood dataset (GSE76705). Additionally, the expression of key genes was validated by quantitative real-time polymerase chain reaction and immunohistochemistry. Results CD19 and POU2AF1 had diagnostic efficacy for COPD and were significantly correlated with lung function and CT indexes of emphysema. Enrichment and immune analyses revealed that CD19 and POU2AF1 were correlated with the B cells in COPD. These results were consistent in GSE47460. The expression of CD19 and POU2AF1 in blood was the opposite of that in lung tissues, and CD19 and POU2AF1 were both significantly upregulated in COPD lung tissues at both the mRNA and protein levels. Conclusion CD19 and POU2AF1 may serve as key regulators of emphysema and contribute to the progression of COPD by regulating the B-cell immunology. Targeting B cells may be a promising strategy for treating COPD.

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Identification of hub genes and key pathways in the emphysema phenotype of COPD

Cited by 13 publications

References 42 publications

Transcriptomic analysis and validation reveal the pathogenesis and a novel biomarker of acute exacerbation of chronic obstructive pulmonary disease

Transcriptomic analysis and validation reveal the pathogenesis and a novel biomarker of acute exacerbation of chronic obstructive pulmonary disease

Blood-Based Transcriptomic and Proteomic Biomarkers of Emphysema

CD19 and POU2AF1 are Potential Immune-Related Biomarkers Involved in the Emphysema of COPD: On Multiple Microarray Analysis

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