Transcriptomic profiles in pulmonary arterial hypertension associate with disease severity and identify novel candidate genes

Romanoski, Casey E.; Qi, Xuchen; Sangam, Shreya; Vanderpool, Rebecca; Stearman, Robert S.; Conklin, Austin C.; Gonzalez-Garay, Manuel L.; Rischard, Franz; Ayon, Ramon J.; Jian, Wang; Simonson, Tatum S.; Babicheva, Aleksandra; Shi, Yingjie; Tang, Haiyang; Kanthi, Yogendra; Geraci, Mark W.; Garcia, Joe G.N.; Yuan, Jason X.‐J.; Desai, Ankit A.

doi:10.1177/2045894020968531

Cited by 12 publications

(10 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The correlations between gene and clinical features observed in the discovery cohort were also examined in our validation cohort of 91 subjects, and also in an external cohort of 32 subjects with RNA collected from PBMCs 26 . We found that 64 of the 90 (71%) correlations measured in these two independent cohorts were consistent with our discovery cohort (Supplementary Table 5 ).…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Biological heterogeneity in idiopathic pulmonary arterial hypertension identified through unsupervised transcriptomic profiling of whole blood

et al. 2021

Self Cite

View full text Add to dashboard Cite

Idiopathic pulmonary arterial hypertension (IPAH) is a rare but fatal disease diagnosed by right heart catheterisation and the exclusion of other forms of pulmonary arterial hypertension, producing a heterogeneous population with varied treatment response. Here we show unsupervised machine learning identification of three major patient subgroups that account for 92% of the cohort, each with unique whole blood transcriptomic and clinical feature signatures. These subgroups are associated with poor, moderate, and good prognosis. The poor prognosis subgroup is associated with upregulation of the ALAS2 and downregulation of several immunoglobulin genes, while the good prognosis subgroup is defined by upregulation of the bone morphogenetic protein signalling regulator NOG, and the C/C variant of HLA-DPA1/DPB1 (independently associated with survival). These findings independently validated provide evidence for the existence of 3 major subgroups (endophenotypes) within the IPAH classification, could improve risk stratification and provide molecular insights into the pathogenesis of IPAH.

show abstract

Section: Resultsmentioning

confidence: 99%

“…The cohort comprised 84 subjects with Group 1 PAH of whom 32 were diagnosed with idiopathic PAH. For each subject, demographics and clinical variables were collected 26 . PBMCs were stored in RNAlater as previously described.…”

Section: Methodsmentioning

confidence: 99%

Biological heterogeneity in idiopathic pulmonary arterial hypertension identified through unsupervised transcriptomic profiling of whole blood

et al. 2021

Self Cite

View full text Add to dashboard Cite

show abstract

“…The GSE117261 dataset (containing lung samples from 58 PAH patients and 25 healthy controls) was obtained from the GEO database ( https://www.ncbi.nlm.nih.gov/geo/ ) and analyzed accordingly [ 22 ]. The expression matrix was annotated with GPL6244, Affymetrix human gene 1.0 ST array (transcription/gene), and normalized using the limma software package and the ‘quantify’ method [ 23 ].…”

Section: Methodsmentioning

confidence: 99%

miR-155-5p regulates hypoxia-induced pulmonary artery smooth muscle cell function by targeting PYGL

2022

View full text Add to dashboard Cite

Pulmonary arterial hypertension (PAH) is a cardiovascular disease that has high incidence and causes massive deaths. miR-155-5p/PYGL pathway was revealed to play a crucial role in PAH by weighted gene co-expression network analysis (WGCNA). The potential mechanism of miR-155-5p in regulating hypoxia-induced pulmonary artery smooth muscle cell (PASMC) function was analyzed through in vitro experiments. Hypoxia treatment stimulated the proliferation of PASMCs and increased the expression of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1α (HIF-1α). At the same time, revealed by qRT-PCR and western blot, the level of miR-155-5p was raised, and the level of PYGL was decreased in hypoxia-induced PASMCs. Through CCK-8 assay, transwell assay and flow cytometry, it was revealed that miR-155-5p inhibitor remarkably inhibited the cell proliferation and migration and decreased the proportion of hypoxia-stimulated PASMCs in S and G2/M phases. Dual-luciferase reporter system was subsequently applied to validate the straight regulation of miR-155-5p on PYGL based on the analysis of online database. Furthermore, siPYGL was revealed to reverse the influence of miR-155-5p inhibitor on hypoxia-induced PASMCs. These outcomes indicate that the increased level of miR-155-5p in hypoxia-stimulated PASMCs could enhance the cell proliferation, cell migration, and cell cycle progression by targeting PYGL directly. This study may supply novel treatment strategies for PAH. Abbreviations : PH, pulmonary hypertension; PAH, pulmonary arterial hypertension; WGCNA, weighted gene co-expression network analysis; PASMCs, pulmonary artery smooth muscle cells; VEGF, vascular endothelial growth factor; HIF-1α, hypoxia-inducible factor-1α; SMCs, smooth muscle cells; DEGs, differentially expressed genes; GEO, Gene Expression Omnibus; GO, Gene Ontology; KEGG, Kyoto Encyclopedia of Genes and Genomes; FBS, fetal bovine serum; OD, optical density; BCA, bicinchoninic acid; PVDF, polyvinylidene fluoride; PBS, phosphate-buffered saline; BP, biological process; MF, molecular function; CC, cell component.

show abstract

“…Microarray expression data (GSE117261) [ 9 , 10 ] was downloaded from the Gene Expression Omnibus (GEO) database ( https://www.ncbi.nlm.nih.gov/geo/ ), representing a GPL6244 Affymetrix Human Gene 1.0 ST Array. GSE117261 includes 57 lung tissue specimens from 32 PAH patients and 25 normal controls.…”

Section: Methodsmentioning

confidence: 99%

“…Microarray expression data (GSE117261) [9,10] was downloaded from the Gene Expression Omnibus (GEO) database (https:// www. ncbi.…”

Section: Data Sourcesmentioning

confidence: 99%

The identification and verification of hub genes associated with pulmonary arterial hypertension using weighted gene co-expression network analysis

Chen

Lin

et al. 2022

BMC Pulm Med

View full text Add to dashboard Cite

Background Pulmonary arterial hypertension (PAH) is characterized by a progressive increase in pulmonary vascular resistance and pulmonary arterial pressure, with complex etiology, difficult treatment and poor prognosis. The objective of this study was to investigate the potential biomarkers for PAH based on bioinformatics analysis. Methods The GSE117261 datasets were downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were identified by screening PAH patients and controls. Then the DEGs were analyzed using a Weighted Gene Co-expression Network Analysis (WGCNA) and the key modules were determined, and to further explore their potential biological functions via Gene Ontology analysis (GO), Kyoto Encyclopedia of Genes and Genomes Pathway analysis (KEGG), and Gene Set Enrichment Analysis (GSEA). Moreover, Protein–protein interaction (PPI) networks were constructed to identify hub gene candidates in the key modules. Finally, real-time quantitative polymerase chain reaction was supplied to detect the expressions of hub genes in human pulmonary arterial smooth cells treated with cobalt chloride (COCl2) which was used to mimic hypoxia. Results There were 2299 DEGs identified. WGCNA indicated that yellow module was the key one correlated with PAH. GO and KEGG analysis demonstrated that genes in the yellow module were mainly enriched in ‘Pathways in cancer’. GSEA revealed that ‘HALLMARK_MYC_TARGETS_V1’ was remarkably enriched in PAH. Based on the PPI network, vascular endothelial growth factor A, proto-oncogene receptor tyrosine kinase (KIT), PNN interacting serine and arginine rich protein (PNISR) and heterogeneous nuclear ribonucleoprotein H1 (HNRNPH1) were identified as the hub genes. Additionally, the PCR indicated that the elevated expressions of PNISR and HNRNPH1 were in line with the bioinformatics analysis. ROC analysis determined that PNISR and HNRNPH1 may be potential biomarkers to provide better diagnosis of PAH. Conclusion PNISR and HNRNPH1 were potential biomarkers to diagnosis PAH. In summary, the identified DEGs, modules, pathways, and hub genes provide clues and shed light on the potential molecular mechanisms of PAH.

show abstract

Transcriptomic profiles in pulmonary arterial hypertension associate with disease severity and identify novel candidate genes

Cited by 12 publications

References 21 publications

Biological heterogeneity in idiopathic pulmonary arterial hypertension identified through unsupervised transcriptomic profiling of whole blood

Biological heterogeneity in idiopathic pulmonary arterial hypertension identified through unsupervised transcriptomic profiling of whole blood

miR-155-5p regulates hypoxia-induced pulmonary artery smooth muscle cell function by targeting PYGL

The identification and verification of hub genes associated with pulmonary arterial hypertension using weighted gene co-expression network analysis

Contact Info

Product

Resources

About