{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T16:05:03Z","timestamp":1791821103714,"version":"4.3.4"},"reference-count":41,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,12,1]],"date-time":"2022-12-01T00:00:00Z","timestamp":1669852800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["U1904142"],"award-info":[{"award-number":["U1904142"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82170037"],"award-info":[{"award-number":["82170037"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cardiovasc. Med."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Molecular biomarkers are widely used for disease diagnosis and exploration of pathogenesis. Pulmonary arterial hypertension (PAH) is a rapidly progressive cardiopulmonary disease with delayed diagnosis. Studies were limited regarding molecular biomarkers correlated with PAH from a broad perspective.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Two independent microarray cohorts comprising 73 PAH samples and 36 normal samples were enrolled in this study. The weighted gene co-expression network analysis (WGCNA) was performed to identify the key modules associated with PAH. The LASSO algorithm was employed to fit a diagnostic model. The latent biology mechanisms and immune landscape were further revealed <jats:italic>via<\/jats:italic> bioinformatics tools.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The WGCNA approach ultimately identified two key modules significantly associated with PAH. For genes within the two models, differential expression analysis between PAH and normal samples further determined nine key genes. With the expression profiles of these nine genes, we initially developed a PAH diagnostic signature (PDS) consisting of LRRN4, PI15, BICC1, PDE1A, TSHZ2, HMCN1, COL14A1, CCDC80, and ABCB1 in GSE117261 and then validated this signature in GSE113439. The ROC analysis demonstrated outstanding AUCs with 0.948 and 0.945 in two cohorts, respectively. Besides, patients with high PDS scores enriched plenty of Th17 cells and neutrophils, while patients with low PDS scores were dramatically related to mast cells and B cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our study established a robust and promising signature PDS for diagnosing PAH, with key genes, novel pathways, and immune landscape offering new perspectives for exploring the molecular mechanisms and potential therapeutic targets of PAH.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fcvm.2022.940894","type":"journal-article","created":{"date-parts":[[2022,12,1]],"date-time":"2022-12-01T15:35:57Z","timestamp":1669908957000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":12,"title":["Construction of a diagnostic signature and immune landscape of pulmonary arterial hypertension"],"prefix":"10.3389","volume":"9","author":[{"given":"Mengjie","family":"Duo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zaoqu","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuyuan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pengfei","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siyuan","family":"Weng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianci","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruhao","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhe","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,12,1]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"104","DOI":"10.1183\/09031936.00092306","article-title":"An epidemiological study of pulmonary arterial hypertension.","volume":"30","author":"Peacock","year":"2007","journal-title":"Eur Respir J."},{"key":"B2","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1164\/rccm.201712-2553OC","article-title":"Fhit, a novel modifier gene in pulmonary arterial hypertension.","volume":"199","author":"Dannewitz Prosseda","year":"2019","journal-title":"Am J Respir Crit Care Med."},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.f2028","article-title":"Pulmonary hypertension: diagnosis and management.","volume":"346","author":"Kiely","year":"2013","journal-title":"BMJ."},{"key":"B4","doi-asserted-by":"publisher","first-page":"2546","DOI":"10.1016\/j.jacc.2006.07.061","article-title":"Complications of right heart catheterization procedures in patients with pulmonary hypertension in experienced centers.","volume":"48","author":"Hoeper","year":"2006","journal-title":"J Am Coll Cardiol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1093\/eurheartj\/ehv317","article-title":"2015 ESC\/ERS guidelines for the diagnosis and treatment of pulmonary hypertension: the joint task force for the diagnosis and treatment of pulmonary hypertension of the European society of cardiology (ESC) and the European respiratory society (ERS): endorsed by: association for European paediatric and congenital cardiology (AEPC), international society for heart and lung transplantation (ISHLT).","volume":"37","author":"Gali\u00e8","year":"2016","journal-title":"Eur Heart J."},{"key":"B6","doi-asserted-by":"publisher","first-page":"258","DOI":"10.1111\/echo.12061","article-title":"The diagnostic accuracy of doppler echocardiography in assessment of pulmonary artery systolic pressure: a meta-analysis.","volume":"30","author":"Taleb","year":"2013","journal-title":"Echocardiography."},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-03672-4","article-title":"Identification of rare sequence variation underlying heritable pulmonary arterial hypertension.","volume":"9","author":"Gr\u00e4f","year":"2018","journal-title":"Nat Commun."},{"key":"B8","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1111\/j.2517-6161.1995.tb02031.x","article-title":"Controlling the false discovery rate: a practical and powerful approach to multiple testing","volume":"57","author":"Benjamini","year":"1995","journal-title":"J R Stat Soc Series B Stat Methodol"},{"key":"B9","doi-asserted-by":"publisher","first-page":"2361","DOI":"10.1056\/NEJMra2000348","article-title":"Pulmonary arterial hypertension.","volume":"385","author":"Hassoun","year":"2021","journal-title":"N Eng J Med."},{"key":"B10","doi-asserted-by":"publisher","first-page":"2250","DOI":"10.1161\/circulationaha.109.192230","article-title":"ACCF\/AHA 2009 expert consensus document on pulmonary hypertension: a report of the American college of cardiology foundation task force on expert consensus documents and the American heart association: developed in collaboration with the American college of chest physicians, American thoracic society, inc., and the pulmonary hypertension association.","volume":"119","author":"McLaughlin","year":"2009","journal-title":"Circulation."},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.j5492","article-title":"Pulmonary arterial hypertension: pathogenesis and clinical management.","volume":"360","author":"Thenappan","year":"2018","journal-title":"BMJ."},{"key":"B12","doi-asserted-by":"publisher","first-page":"3514","DOI":"10.1172\/jci74773","article-title":"Systems-level regulation of microrna networks by miR-130\/301 promotes pulmonary hypertension.","volume":"124","author":"Bertero","year":"2014","journal-title":"J Clin Invest."},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1186\/s12931-017-0631-9","article-title":"Using omics approaches to understand pulmonary diseases.","volume":"18","author":"Kan","year":"2017","journal-title":"Respir Res."},{"key":"B14","doi-asserted-by":"publisher","first-page":"1104","DOI":"10.1111\/resp.13557","article-title":"Osteopontin lung gene expression is a marker of disease severity in pulmonary arterial hypertension.","volume":"24","author":"Mura","year":"2019","journal-title":"Respirology."},{"key":"B15","doi-asserted-by":"publisher","first-page":"637","DOI":"10.1165\/rcmb.2018-0368OC","article-title":"Systems analysis of the human pulmonary arterial hypertension lung transcriptome.","volume":"60","author":"Stearman","year":"2019","journal-title":"Am J Respir Cell Mol Biol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"H1322","DOI":"10.1152\/ajpheart.00136.2018","article-title":"Role of extracellular matrix in the pathogenesis of pulmonary arterial hypertension.","volume":"315","author":"Thenappan","year":"2018","journal-title":"Am J Physiol Heart Circ Physiol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1165\/rcmb.2021-0091TR","article-title":"Basement membrane extracellular matrix proteins in pulmonary vascular and right ventricular remodeling in pulmonary hypertension.","volume":"65","author":"Ambade","year":"2021","journal-title":"Am J Respir Cell Mol Biol."},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1186\/s12929-017-0359-3","article-title":"Baicalin attenuates chronic hypoxia-induced pulmonary hypertension via adenosine A(2A) receptor-induced SDF-1\/CXCR4\/PI3K\/AKT signaling.","volume":"24","author":"Huang","year":"2017","journal-title":"J Biomed Sci."},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1111\/cpr.12436","article-title":"The transient receptor potential vanilloid-3 regulates hypoxia-mediated pulmonary artery smooth muscle cells proliferation via PI3K\/AKT signaling pathway.","volume":"51","author":"Zhang","year":"2018","journal-title":"Cell Prolif."},{"key":"B20","doi-asserted-by":"publisher","first-page":"1560","DOI":"10.1016\/j.ajpath.2011.05.051","article-title":"Neutrophil elastase is produced by pulmonary artery smooth muscle cells and is linked to neointimal lesions.","volume":"179","author":"Kim","year":"2011","journal-title":"Am J Pathol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"1442","DOI":"10.1016\/j.chest.2021.06.028","article-title":"Severe pulmonary arterial hypertension is characterized by increased neutrophil elastase and relative elafin deficiency.","volume":"160","author":"Sweatt","year":"2021","journal-title":"Chest."},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.3389\/fmed.2018.00217","article-title":"The role of neutrophils and neutrophil elastase in pulmonary arterial hypertension.","volume":"5","author":"Taylor","year":"2018","journal-title":"Front Med."},{"key":"B23","doi-asserted-by":"publisher","first-page":"2078","DOI":"10.1161\/atvbaha.116.307634","article-title":"Neutrophil extracellular traps promote angiogenesis: evidence from vascular pathology in pulmonary hypertension.","volume":"36","author":"Aldabbous","year":"2016","journal-title":"Arterioscler Thromb Vasc Biol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"1047","DOI":"10.1093\/abbs\/gmx095","article-title":"Immune cells and autoantibodies in pulmonary arterial hypertension.","volume":"49","author":"Li","year":"2017","journal-title":"Acta Biochim Biophys Sin."},{"key":"B25","doi-asserted-by":"publisher","first-page":"351","DOI":"10.1007\/978-3-030-63046-1_19","article-title":"Inflammation in pulmonary arterial hypertension.","volume":"1303","author":"Klouda","year":"2021","journal-title":"Adv Exp Med Biol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1080\/15548627.2017.1389823","article-title":"Autophagy and inflammation in chronic respiratory disease.","volume":"14","author":"Racanelli","year":"2018","journal-title":"Autophagy."},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.3389\/fcvm.2021.624714","article-title":"Identification of potential biomarkers and immune infiltration characteristics in idiopathic pulmonary arterial hypertension using bioinformatics analysis.","volume":"8","author":"Zeng","year":"2021","journal-title":"Front Cardiovasc Med."},{"key":"B28","doi-asserted-by":"publisher","first-page":"2576","DOI":"10.1080\/21655979.2021.1936816","article-title":"Screening of key biomarkers and immune infiltration in pulmonary arterial hypertension via integrated bioinformatics analysis.","volume":"12","author":"Zeng","year":"2021","journal-title":"Bioengineered."},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.3390\/genes12010125","article-title":"Identification of potential risk genes and the immune landscape of idiopathic pulmonary arterial hypertension via microarray gene expression dataset reanalysis.","volume":"12","author":"Xu","year":"2021","journal-title":"Genes."},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2021.107858","article-title":"Role of phosphodiesterase 1 in the pathophysiology of diseases and potential therapeutic opportunities.","volume":"226","author":"Samidurai","year":"2021","journal-title":"Pharmacol Ther."},{"key":"B31","doi-asserted-by":"publisher","first-page":"2331","DOI":"10.1161\/circulationaha.106.676809","article-title":"Phosphodiesterase 1 upregulation in pulmonary arterial hypertension: target for reverse-remodeling therapy.","volume":"115","author":"Schermuly","year":"2007","journal-title":"Circulation."},{"key":"B32","doi-asserted-by":"publisher","first-page":"L1002","DOI":"10.1152\/ajplung.00383.2014","article-title":"Compartment-specific expression of collagens and their processing enzymes in intrapulmonary arteries of IPAH patients.","volume":"308","author":"Hoffmann","year":"2015","journal-title":"Am J Physiol Lung Cell Mol Physiol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"865","DOI":"10.1210\/er.2008-0032","article-title":"The Cap superfamily: cysteine-rich secretory proteins, antigen 5, and pathogenesis-related 1 proteins \u2013 roles in reproduction, cancer, and immune defense.","volume":"29","author":"Gibbs","year":"2008","journal-title":"Endocr Rev."},{"key":"B34","doi-asserted-by":"publisher","first-page":"418","DOI":"10.1152\/physiolgenomics.00004.2014","article-title":"Protease inhibitor 15, a candidate gene for abdominal aortic internal elastic lamina ruptures in the Rat.","volume":"46","author":"Falak","year":"2014","journal-title":"Physiol Genom."},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2016.00337","article-title":"The role of leucine-rich repeat containing protein 10 (LRRC10) in dilated cardiomyopathy.","volume":"7","author":"Brody","year":"2016","journal-title":"Front Physiol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"160","DOI":"10.1093\/cvr\/cvu243","article-title":"Physiological activation of Akt by PHLPP1 deletion protects against pathological hypertrophy.","volume":"105","author":"Moc","year":"2015","journal-title":"Cardiovasc Res."},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2020.106828","article-title":"BICC1 as a novel prognostic biomarker in gastric cancer correlating with immune infiltrates.","volume":"87","author":"Zhao","year":"2020","journal-title":"Int Immunopharmacol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"303","DOI":"10.1093\/intimm\/dxp001","article-title":"Fibulin-6 expression and anoikis in human salivary gland epithelial cells: implications in sjogren\u2019s syndrome.","volume":"21","author":"Sisto","year":"2009","journal-title":"Int Immunol."},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-021-96824-4","article-title":"Hemicentin-1 is an essential extracellular matrix component of the dermal-epidermal and myotendinous junctions.","volume":"11","author":"Welcker","year":"2021","journal-title":"Sci Rep."},{"key":"B40","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1016\/j.ajpath.2012.03.044","article-title":"Th17 cells: biology, pathogenesis of autoimmune and inflammatory diseases, and therapeutic strategies.","volume":"181","author":"Maddur","year":"2012","journal-title":"Am J Pathol."},{"key":"B41","doi-asserted-by":"publisher","first-page":"L927","DOI":"10.1152\/ajplung.00049.2011","article-title":"Eosinophils are necessary for pulmonary arterial remodeling in a mouse model of eosinophilic inflammation-induced pulmonary hypertension.","volume":"301","author":"Weng","year":"2011","journal-title":"Am J Physiol Lung Cell Mol Physiol."}],"container-title":["Frontiers in Cardiovascular Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcvm.2022.940894\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,1]],"date-time":"2022-12-01T15:36:02Z","timestamp":1669908962000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcvm.2022.940894\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,1]]},"references-count":41,"alternative-id":["10.3389\/fcvm.2022.940894"],"URL":"https:\/\/doi.org\/10.3389\/fcvm.2022.940894","relation":{},"ISSN":["2297-055X"],"issn-type":[{"value":"2297-055X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,1]]},"article-number":"940894"}}