Dataset Information

Identification and Validation of Key Genes Associated With Systemic Sclerosis-Related Pulmonary Hypertension.

ABSTRACT: Systemic sclerosis-associated with pulmonary arterial hypertension (SSc-PAH) is still a major cause of SSc related deaths. Early diagnosis and prompt treatment are crucial to reduce the mortality of patients with SSc-PAH. To screen the candidate biomarkers and potential therapeutic targets for SSc-PAH, we analyzed the data set (GSE33463 and GSE19617) for confirming key genes in peripheral blood mononuclear cells from SSc-PAH patients. A total of 105 SSc patients from gene expression omnibus (GEO) were included as discovery cohort (n = 69) and duplication cohort (n = 36) for screening hub genes by weighted gene co-expression network analysis (WGCNA). Furthermore, an independent validation cohort (n = 40), including healthy controls, SSc and SSc-PAH patients, was used for further validation by quantitative real-time polymerase chain reaction. The results showed that four key genes, including IFIT2, IFIT3, RSAD2, and PARP14, may serve as potential biomarkers in SSc-PAH. Also, they could be independent risk factors for SSc-PAH. In conclusion, the four key genes can be expected to become the potential therapeutic targets and early biomarkers for accurate therapy and diagnosis of SSc-PAH in the future, which also provides promising insights into the pathogenesis of SSc-PAH at the molecular level.

SUBMITTER: Zheng JN

PROVIDER: S-EPMC7393672 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Identification and Validation of Key Genes Associated With Systemic Sclerosis-Related Pulmonary Hypertension.

Zheng Ji-Na JN Li Yang Y Yan Yue-Mei YM Shi Hui H Zou Tian-Tian TT Shao Wen-Qi WQ Wang Qiang Q

Frontiers in genetics 20200724

Systemic sclerosis-associated with pulmonary arterial hypertension (SSc-PAH) is still a major cause of SSc related deaths. Early diagnosis and prompt treatment are crucial to reduce the mortality of patients with SSc-PAH. To screen the candidate biomarkers and potential therapeutic targets for SSc-PAH, we analyzed the data set (GSE33463 and GSE19617) for confirming key genes in peripheral blood mononuclear cells from SSc-PAH patients. A total of 105 SSc patients from gene expression omnibus (GEO ...[more]

PMID: 32793290

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Project description:Systemic sclerosis (SSc) is the most common connective tissue disease causing pulmonary hypertension (PAH). However, the cause and potential immune molecular events associated with PAH are still unclear. Therefore, it is particularly essential to analyze the changes in SSc-PAH-related immune cells and their immune-related genes. Three microarray datasets (GSE22356, GSE33463, and GSE19617) were obtained by the Gene Expression Omnibus (GEO). Compared with SSc, we found neutrophils have a statistically higher abundance, while T-cell CD4 naive and T-cell CD4 memory resting have a statistically lower abundance in peripheral blood mononuclear cells (PBMCs). Moreover, the results of Gene Set Enrichment Analysis (GSEA) showed there is a differential enrichment of multiple pathways between SSc and SSc-PAH. By combining differentiated expressed genes (DEGs) and immune-related genes (IRGs), fifteen IRGs were selected. In addition, we also analyzed the first five rich Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and the most abundant Gene Ontology (GO)-molecular functional terms. Furthermore, interleukin-7 receptor (IL-7R), tyrosine-protein kinase (LCK), histone deacetylase 1 (HDAC1), and epidermal growth factor receptor (EGFR) genes were identified as hub genes via protein-protein interaction (PPI) network analysis. The Comparative Toxic Genomics Database (CTD) analysis result showed that LCK, HDAC1, and EGFR have a higher score with SSc. Coexpression network analysis confirmed that IL-7R, LCK, and HDAC1 are key genes related to immune regulation in SSc without PAH and are involved in T-cell immune regulation. Subsequently, using GSE22356 and GSE33463 as the test sets and GSE19617 as the verification set, it was verified that the mRNA expression levels of the three central genes of SSc-PAH were significantly lower than those of the SSc without PAH samples. Consistent with previous predictions, the expressions of IL-7R, LCK, and HDAC1 are positively correlated with the numbers of T-cell CD4 naive and T-cell CD4 memory, while the expressions of IL-7R and LCK are negatively correlated with the numbers of neutrophils in the peripheral blood. Therefore, this evidence may suggest that these three immune-related genes: IL-7R, LCK, and HDAC1, may be highly related to the immunological changes in SSc-PAH. These three molecules can reduce T cells in SSc-PAH PBMCs through the regulation of T-cell activation, which suggests that these three molecules may be involved in the development of SSc-PAH. Meanwhile, the low expression of IL-7R, LCK, and HDAC1 detected in the peripheral blood of SSc may indicate the possibility of PAH and hopefully become a biomarker for the early detection of SSc-PAH. Finally, 49 target miRNAs of 3 specifically expressed hub genes were obtained, and 49 mRNA-miRNA pairs were identified, which provided directions for our further research.

Project description:BackgroundThe role of microRNAs (miRNAs) in the pathogenesis of systemic sclerosis-associated pulmonary arterial hypertension (SSc-PAH) remains to be fully elucidated. This study evaluated the expression profile of miRNAs in the lung tissue of patients with SSc-PAH.MethodsLung tissue samples were collected from 3 SSc-PAH patients and 4 healthy controls. A small RNA high throughput sequence approach was used for screening the differentially expressed miRNAs in the lung tissue samples. Real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to validate 4 highly significant differentially expressed miRNAs. Gene Ontology and KEGG (Kyoto Encyclopedia of Genes and Genomes) enrichment analysis for mRNAs were performed using the R package clusterProfiler software.ResultsA total of 82 upregulated miRNAs and 35 downregulated miRNAs were detected in the lung tissues of patients with SSc-PAH compared with healthy controls. GO enrichment analysis demonstrated that the upregulated target genes were closely involved in biological processes such as nervous system development, anatomical structure morphogenesis, system development, cellular macromolecule metabolic processes, and cellular processes. The downregulated target genes were involved in the plasma membrane bound cell projection morphogenesis and the regulation of macromolecule metabolic processes. The KEGG enrichment analysis showed that the upregulated genes were associated with important pathways involved in cancer biology, and the target genes of the downregulated miRNAs were involved in axon guidance. High throughput sequencing and qRT-PCR revealed that hsa-miR-205-5p and hsa-miR-539-3p were differentially expressed in SSc-PAH tissue. The target genes of hsa-miR-205-5p and hsa-miR-539-3p, IRF1and ADCYAP1, respectively, were verified using the high throughput dataset GSE48149.ConclusionsmiRNAs may play an important role in the pathogenesis of SSc-PAH, and hsa-miR-205-5p and hsa-miR-539-3p may be potential therapeutic targets in patients with SSc-PAH.

Dataset Information

Identification and Validation of Key Genes Associated With Systemic Sclerosis-Related Pulmonary Hypertension.

Publications

Identification and Validation of Key Genes Associated With Systemic Sclerosis-Related Pulmonary Hypertension.

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