scholarly journals Expression Quantitative Trait Locus Mapping in Pulmonary Arterial Hypertension

Genes ◽  
2020 ◽  
Vol 11 (11) ◽  
pp. 1247
Author(s):  
Anna Ulrich ◽  
Pablo Otero-Núñez ◽  
John Wharton ◽  
Emilia M. Swietlik ◽  
Stefan Gräf ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Quantitative Trait ◽  
Association Studies ◽  
Enrichment Analysis ◽  
Functional Enrichment Analysis ◽  
Population Based ◽  
Functional Enrichment ◽  
Eqtl Mapping ◽  
Pulmonary Arterial

Expression quantitative trait loci (eQTL) can provide a link between disease susceptibility variants discovered by genetic association studies and biology. To date, eQTL mapping studies have been primarily conducted in healthy individuals from population-based cohorts. Genetic effects have been known to be context-specific and vary with changing environmental stimuli. We conducted a transcriptome- and genome-wide eQTL mapping study in a cohort of patients with idiopathic or heritable pulmonary arterial hypertension (PAH) using RNA sequencing (RNAseq) data from whole blood. We sought confirmation from three published population-based eQTL studies, including the GTEx Project, and followed up potentially novel eQTL not observed in the general population. In total, we identified 2314 eQTL of which 90% were cis-acting and 75% were confirmed by at least one of the published studies. While we observed a higher GWAS trait colocalization rate among confirmed eQTL, colocalisation rate of novel eQTL reported for lung-related phenotypes was twice as high as that of confirmed eQTL. Functional enrichment analysis of genes with novel eQTL in PAH highlighted immune-related processes, a suspected contributor to PAH. These potentially novel eQTL specific to or active in PAH could be useful in understanding genetic risk factors for other diseases that share common mechanisms with PAH.

scholarly journals Identification of Hub Genes and MicroRNAs Associated With Idiopathic Pulmonary Arterial Hypertension by Integrated Bioinformatics Analyses

2021 ◽  
Vol 12 ◽  
Author(s):  
Xue Qiu ◽  
Jinyan Lin ◽  
Bixiao Liang ◽  
Yanbing Chen ◽  
Guoqun Liu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Enrichment Analysis ◽  
Functional Enrichment Analysis ◽  
Idiopathic Pulmonary Arterial Hypertension ◽  
Functional Enrichment ◽  
Hub Genes ◽  
Ppi Networks ◽  
Pulmonary Arterial

ObjectiveThe aim of this study is the identification of hub genes associated with idiopathic pulmonary arterial hypertension (IPAH).Materials and MethodsGSE15197 gene expression data was downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified by screening IPAH patients and controls. The 5,000 genes with the greatest variances were analyzed using a weighted gene co-expression network analysis (WGCNA). Modules with the strongest correlation with IPAH were chosen, followed by a functional enrichment analysis. Protein–protein interaction (PPI) networks were constructed to identify hub gene candidates using calculated degrees. Real hub genes were found from the overlap of DEGs and candidate hub genes. microRNAs (miRNAs) targeting real hub genes were found by screening miRNet 2.0. The most important IPAH miRNAs were identified.ResultsThere were 4,395 DEGs identified. WGCNA indicated that green and brown modules associated most strongly with IPAH. Functional enrichment analysis showed that green and brown module genes were mainly involved in protein digestion and absorption and proteoglycans in cancer, respectively. The top ten candidate hub genes in green and brown modules were identified, respectively. After overlapping with DEGs, 11 real hub genes were identified: EP300, MMP2, CDH2, CDK2, GNG10, ALB, SMC2, DHX15, CUL3, BTBD1, and LTN1. These genes were expressed with significant differences in IPAH versus controls, indicating a high diagnostic ability. The miRNA–gene network showed that hsa-mir-1-3p could associate with IPAH.ConclusionEP300, MMP2, CDH2, CDK2, GNG10, ALB, SMC2, DHX15, CUL3, BTBD1, and LTN1 may play essential roles in IPAH. Predicted miRNA hsa-mir-1-3p could regulate gene expression in IPAH. Such hub genes may contribute to the pathology and progression in IPAH, providing potential diagnostic and therapeutic opportunities for IPAH patients.

scholarly journals Elucidation of the mechanisms and molecular targets of Qishen Yiqi formula for the treatment of pulmonary arterial hypertension using a bioinformatics/network topology-based strategy

2020 ◽  
Vol 23 ◽  
Author(s):  
Peiliang Wu ◽  
Xiaona Xie ◽  
Mayun Chen ◽  
Junwei Sun ◽  
Luqiong Cai ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Network Topology ◽  
Molecular Mechanisms ◽  
Molecular Targets ◽  
Enrichment Analysis ◽  
Network Pharmacology ◽  
Pathway Enrichment Analysis ◽  
Bioactive Ingredients ◽  
Pulmonary Arterial

Background and Objective: Qishen Yiqi formula (QSYQ) is used to treat cardiovascular disease in the clinical practice of traditional Chinese medicine. However, few studies have explored whether QSYQ affects pulmonary arterial hypertension (PAH), and the mechanisms of action and molecular targets of QSYQ for the treatment of PAH are unclear. A bioinformatics/network topology-based strategy was used to identify the bioactive ingredients, putative targets, and molecular mechanisms of QSYQ in PAH. Methods: A network pharmacology-based strategy was employed by integrating active component gathering, target prediction, PAH gene collection, network topology, and gene enrichment analysis to systematically explore the multicomponent synergistic mechanisms. Results: In total, 107 bioactive ingredients of QSYQ and 228 ingredient targets were identified. Moreover, 234 PAH-related differentially expressed genes with a |fold change| >2 and an adjusted P value < 0.005 were identified between the PAH patient and control groups, and 266 therapeutic targets were identified. The pathway enrichment analysis indicated that 85 pathways, including the PI3K-Akt, MAPK, and HIF-1 signaling pathways, were significantly enriched. TP53 was the core target gene, and 7 other top genes (MAPK1, RELA, NFKB1, CDKN1A, AKT1, MYC, and MDM2) were the key genes in the gene-pathway network based on the effects of QSYQ on PAH. Conclusion: An integrative investigation based on network pharmacology may elucidate the multicomponent synergistic mechanisms of QSYQ in PAH and lay a foundation for further animal experiments, human clinical trials and rational clinical applications of QSYQ.

Abstract 14257: Endothelial SOX17 Deficiency Induces Pulmonary Arterial Hypertension

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Zhiyu Dai ◽  
Dan Yi ◽  
BIN LIU ◽  
Shuai Li
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Vascular Remodeling ◽  
Molecular Mechanisms ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Sequencing Analysis ◽  
Pulmonary Arterial

Introduction: Pulmonary arterial hypertension (PAH) is a disaster disease characterized by obliterative vascular remodeling and persistent increase of vascular resistance, leading to right heart failure and premature death. Understanding the cellular and molecular mechanisms will help develop novel therapeutic approaches for PAH patients. Hypothesis: Human genome-wide association studies identified that SOX17 locus variants are associated with PAH. SOX17 mutation is also found in patients with PAH. We hypothesis that endothelial SOX17 deficiency contributes to the pathogenesis of PAH. Methods: Mice with EndoSCL-CreERT mediated deletion of Sox17 ( Sox17 iCKO ) were generated. Sox17 iCKO and Sox17 f/f mice after tamoxifen injection were incubated with hypoxia (10% O 2 ) for 3 weeks to induced PAH. Hemodynamics and histological examination were measured to determine the PAH phenotypes and vascular remodeling. EC proliferation and apoptosis were assessed in SiRNA-mediated SOX17 knockdown in human lung microvascular endothelial cells (hLMVECs). The RNA-sequencing analysis was performed to understand the molecular mechanisms of SOX17 deficiency in ECs. Results: Sox17 iCKO mice exhibited exaggerative PAH evident by the increase of RVSP and RV hypertrophy after hypoxia treatment compared to Sox17 f/f WT mice. SOX17 knockdown in hLMVECs induced cell proliferation and reduced starvation-induced apoptosis. RNA-seq analysis and DAVID pathway analysis demonstrated that there was dysregulation of cell proliferation-related genes, which are enriched in the pathways related to cell cycle, cell division, and mitotic cell cycle. Transcriptional factor, target, and motif discovery analysis of the dysregulated gene set revealed the involvement of transcriptional factors FOXM1 and E2F1. siRNA mediated knockdown of E2F1 but not FOXM1 normalized SOX17 deficiency-induced hLMVECs proliferation and anti-apoptosis. Conclusions: Our study demonstrated that endothelial SOX17 deficiency exaggerates hypoxia-induced PAH. Loss of SOX17 promotes EC proliferation and anti-apoptosis via the upregulation of transcription factor E2F1.

Prognostic impact of pulmonary arterial hypertension: A population-based analysis

2008 ◽  
Vol 124 (2) ◽  
pp. 183-187 ◽  
Author(s):  
Melinda Carrington ◽  
Niamh F. Murphy ◽  
Geoff Strange ◽  
Andrew Peacock ◽  
John J.V. McMurray ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Population Based ◽  
Prognostic Impact ◽  
Pulmonary Arterial

scholarly journals Pulmonary arterial hypertension associated with interferon therapy: a population-based study

2017 ◽  
Vol 12 ◽  
Author(s):  
Ravikanth Papani ◽  
Alexander G. Duarte ◽  
Yu-li Lin ◽  
Yong-Fang Kuo ◽  
Gulshan Sharma
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Interferon Therapy ◽  
Rare Event ◽  
Population Based ◽  
Interferon Α ◽  
Coding System ◽  
Common Procedure ◽  
Pulmonary Arterial

Background: Isolated cases of pulmonary arterial hypertension (PAH) with interferon α or β therapy have been reported, but no population-based estimates of the incidence of the disease after interferon exposure are available. The aim of this study was to determine the incidence of PAH after initiation of interferon therapy, using a large commercial insurance database. Methods: Using National Drug Codes (NDCs) and Healthcare Common Procedure Coding System (HCPCS) codes, we utilized the Clinformatics™ Data Mart (CDM) database to identify subjects between 20 and 65 years old who received α or β interferon therapy between April 2001 and December 2012. Patients were followed from one year prior to the first medication claim for interferon to the first diagnosis of pulmonary hypertension using ICD-9-CM codes 416.0 and 416.8, or disenrollment. In those subjects diagnosed with pulmonary hypertension, a prescription for PAH-specific medications was used as a surrogate endpoint. Results: We identified 20,113 subjects who received interferon therapy during the study period. The median follow-up was 20 months. Pulmonary hypertension occurred in 71 subjects, and PAH-specific medications were prescribed to 7 of these subjects. Conclusion: Although our analysis showed that the development of PAH is a rare event with

scholarly journals Screening of Hub Genes Associated with Pulmonary Arterial Hypertension by Integrated Bioinformatic Analysis

2021 ◽  
Vol 2021 ◽  
pp. 1-16
Author(s):  
Yu Zeng ◽  
Nanhong Li ◽  
Zhenzhen Zheng ◽  
Riken Chen ◽  
Min Peng ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Drug Targets ◽  
Bioinformatic Analysis ◽  
Functional Enrichment ◽  
Receptor Interaction ◽  
Ppi Network ◽  
Hub Genes ◽  
Network Analyses ◽  
Pulmonary Arterial

Background. Pulmonary arterial hypertension (PAH) is a disease or pathophysiological syndrome which has a low survival rate with abnormally elevated pulmonary artery pressure caused by known or unknown reasons. In addition, the pathogenesis of PAH is not fully understood. Therefore, it has become an urgent matter to search for clinical molecular markers of PAH, study the pathogenesis of PAH, and contribute to the development of new science-based PAH diagnosis and targeted treatment methods. Methods. In this study, the Gene Expression Omnibus (GEO) database was used to downloaded a microarray dataset about PAH, and the differentially expressed genes (DEGs) between PAH and normal control were screened out. Moreover, we performed the functional enrichment analyses and protein-protein interaction (PPI) network analyses of the DEGs. In addition, the prediction of miRNA and transcriptional factor (TF) of hub genes and construction miRNA-TF-hub gene network were performed. Besides, the ROC curve was used to evaluate the diagnostic value of hub genes. Finally, the potential drug targets for the 5 identified hub genes were screened out. Results. 69 DEGs were identified between PAH samples and normal samples. GO and KEGG pathway analyses revealed that these DEGs were mostly enriched in the inflammatory response and cytokine-cytokine receptor interaction, respectively. The miRNA-hub genes network was conducted subsequently with 131 miRNAs, 7 TFs, and 5 hub genes (CCL5, CXCL12, VCAM1, CXCR1, and SPP1) which screened out via constructing the PPI network. 17 drugs interacted with 5 hub genes were identified. Conclusions. Through bioinformatic analysis of microarray data sets, 5 hub genes (CCL5, CXCL12, VCAM1, CXCR1, and SPP1) were identified from DEGs between control samples and PAH samples. Studies showed that the five hub genes might play an important role in the development of PAH. These 5 hub genes might be potential biomarkers for diagnosis or targets for the treatment of PAH. In addition, our work also indicated that paying more attention on studies based on these 5 hub genes might help to understand the molecular mechanism of the development of PAH.

scholarly journals Comprehensive bioinformatic analysis identified m6A methylation as an important regulator in mediating immune response during idiopathic pulmonary arterial hypertension

2020 ◽  
Author(s):  
Na Liu ◽  
Yunhong Zeng ◽  
Ting Huang ◽  
Wanyun Zuo ◽  
Yunbin Xiao ◽  
...  
Keyword(s):  
Immune Response ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Immune Cell ◽  
Enrichment Analysis ◽  
Bioinformatic Analysis ◽  
Pathway Enrichment Analysis ◽  
Protein Protein Interaction ◽  
M1 Macrophage ◽  
Pulmonary Arterial

Abstract BackgroundDespite its functional importance in various fundamental bioprocesses, studies of N6-methyladenosine (m6A) in the pulmonary arterial hypertension (PAH) are lacking. Here we studied the potential relevance of m6A RNA methylation and immune response in PAH development.MethodsWe constructed a monocrotaline (MCT) induced PAH rat model and performed Methylated RNA immunoprecipitation sequencing (MeRIP-Seq). The 18 idiopathic PAH (IPAH) microarray data obtained from the GEO database was used to construct co-expression networks by weighted gene co-expression network analysis (WGCNA). CIBERSORT was used to investigate the effect of m6A methylation on immune cell infiltration during PAH.ResultsA differential pattern of m6A abundance, mainly up-methylation, was observed in the lung tissues of rats with MCT induced PAH. By WGCNA, multi-list pathway enrichment analysis and protein-protein interaction (PPI) analysis, we found that m6A methylation modification may play important roles in mediating immune response during PAH. CYBERSORT algorithm indicated that the m6A methylation can drive monocyte to form M1 macrophage, which may be mediated by CCR5 and CXCL9.ConclusionCollectively, m6A landscape is altered in PAH. We summarize newly discovered m6A in controlling immune response, which caused activation of M1 macrophage during PAH. It’s provided a novel insight into the therapeutic mechanisms of PAH.

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