{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T15:33:32Z","timestamp":1792510412485,"version":"4.5.0"},"reference-count":37,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2014,12,1]],"date-time":"2014-12-01T00:00:00Z","timestamp":1417392000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,12,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Rationale<\/jats:title>\n                    <jats:p>Although asthma is recognized as a heterogeneous disease associated with clinical phenotypes, the molecular basis of these phenotypes remains poorly understood. Although genomic studies have successfully broadened our understanding in diseases such as cancer, they have not been widely used in asthma studies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>To link gene expression patterns to clinical asthma phenotypes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We used a microarray platform to analyze bronchial airway epithelial cell gene expression in relation to the asthma biomarker fractional exhaled nitric oxide (FeNO) in 155 subjects with asthma and healthy control subjects from the Severe Asthma Research Program (SARP).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Measurements and Main Results<\/jats:title>\n                    <jats:p>We first identified a diverse set of 549 genes whose expression correlated with FeNO. We used k-means to cluster the patient samples according to the expression of these genes, identifying five asthma clusters\/phenotypes with distinct clinical, physiological, cellular, and gene transcription characteristics\u2014termed \u201csubject clusters\u201d (SCs). To then investigate differences in gene expression between SCs, a total of 1,384 genes were identified that highly differentiated the SCs at an unadjusted P value\u2009&amp;lt;\u200910\u22126. Hierarchical clustering of these 1,384 genes identified nine gene clusters or \u201cbiclusters,\u201d whose coexpression suggested biological characteristics unique to each SC. Although genes related to type 2 inflammation were present, novel pathways, including those related to neuronal function, WNT pathways, and actin cytoskeleton, were noted.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These findings show that bronchial epithelial cell gene expression, as related to the asthma biomarker FeNO, can identify distinct asthma phenotypes, while also suggesting the presence of underlying novel gene pathways relevant to these phenotypes.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1164\/rccm.201406-1099oc","type":"journal-article","created":{"date-parts":[[2014,10,22]],"date-time":"2014-10-22T17:19:16Z","timestamp":1413998356000},"page":"1363-1372","source":"Crossref","is-referenced-by-count":191,"title":["Gene Expression in Relation to Exhaled Nitric Oxide Identifies Novel Asthma Phenotypes with Unique Biomolecular Pathways"],"prefix":"10.1093","volume":"190","author":[{"given":"Brian D.","family":"Modena","sequence":"first","affiliation":[{"name":"Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, University of Pittsburgh Asthma Institute at UPMC, Pittsburgh, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John R.","family":"Tedrow","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, University of Pittsburgh Asthma Institute at UPMC, Pittsburgh, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jadranka","family":"Milosevic","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, University of Pittsburgh Asthma Institute at UPMC, Pittsburgh, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugene R.","family":"Bleecker","sequence":"additional","affiliation":[{"name":"Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston Salem, North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deborah A.","family":"Meyers","sequence":"additional","affiliation":[{"name":"Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston Salem, North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Wu","sequence":"additional","affiliation":[{"name":"Lane Center for Computational Biology School of Computer Science, Carnegie Mellon University, Pittsburgh, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziv","family":"Bar-Joseph","sequence":"additional","affiliation":[{"name":"Lane Center for Computational Biology School of Computer Science, Carnegie Mellon University, Pittsburgh, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serpil C.","family":"Erzurum","sequence":"additional","affiliation":[{"name":"Department of Pathobiology Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin M.","family":"Gaston","sequence":"additional","affiliation":[{"name":"Division of Pediatric Pulmonary, Allergy, and Immunology, Case Western Reserve University and Rainbow Babies and Children\u2019s Hospital, Cleveland, Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William W.","family":"Busse","sequence":"additional","affiliation":[{"name":"Division of Allergy, Pulmonary, and Critical Care Medicine, University of Wisconsin, Madison, Wisconsin; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nizar N.","family":"Jarjour","sequence":"additional","affiliation":[{"name":"Division of Allergy, Pulmonary, and Critical Care Medicine, University of Wisconsin, Madison, Wisconsin; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naftali","family":"Kaminski","sequence":"additional","affiliation":[{"name":"Pulmonary, Critical Care, and Sleep Medicine, Yale School of Medicine, New Haven, Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sally E.","family":"Wenzel","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, University of Pittsburgh Asthma Institute at UPMC, Pittsburgh, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2014,12,1]]},"reference":[{"key":"2026032100265522100_bib1","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1111\/j.1398-9995.2006.01254.x","article-title":"Extent, patterns, and burden of uncontrolled disease in severe or difficult-to-treat asthma","volume":"62","author":"Sullivan","year":"2007","journal-title":"Allergy"},{"key":"2026032100265522100_bib2","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1183\/09031936.00202013","article-title":"International ERS\/ATS guidelines on definition, evaluation and treatment of severe asthma","volume":"43","author":"Chung","year":"2014","journal-title":"Eur Respir J"},{"key":"2026032100265522100_bib3","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1016\/j.jaci.2010.11.015","article-title":"National Institutes of Health\/National Heart, Lung, and Blood Institute Severe Asthma Research Program. Heterogeneity of severe asthma in childhood: Confirmation by cluster analysis of children in the National Institutes of Health\/National Heart, Lung, and Blood Institute Severe Asthma Research Program","volume":"127","author":"Fitzpatrick","year":"2011","journal-title":"J Allergy Clin Immunol"},{"key":"2026032100265522100_bib4","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1164\/rccm.200711-1754OC","article-title":"Cluster analysis and clinical asthma phenotypes","volume":"178","author":"Haldar","year":"2008","journal-title":"Am J Respir Crit Care Med"},{"key":"2026032100265522100_bib5","first-page":"A1877","article-title":"Using spectral clustering of phenotypes to identify novel asthma subtypes [abstract]","volume":"181","author":"Judie","year":"2010","journal-title":"Am J Respir Crit Care Med"},{"key":"2026032100265522100_bib6","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1164\/rccm.200906-0896OC","article-title":"Identification of asthma phenotypes using cluster analysis in the Severe Asthma Research Program","volume":"181","author":"Moore","year":"2010","journal-title":"Am J Respir Crit Care Med"},{"key":"2026032100265522100_bib7","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1183\/09031936.00120810","article-title":"Identifying adult asthma phenotypes using a clustering approach","volume":"38","author":"Siroux","year":"2011","journal-title":"Eur Respir J"},{"key":"2026032100265522100_bib8","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1183\/09031936.00123909","article-title":"Genetic and environmental influences on objective intermediate asthma phenotypes in Dutch twins","volume":"36","author":"Wu","year":"2010","journal-title":"Eur Respir J"},{"key":"2026032100265522100_bib9","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1126\/science.286.5439.531","article-title":"Molecular classification of cancer: class discovery and class prediction by gene expression monitoring","volume":"286","author":"Golub","year":"1999","journal-title":"Science"},{"key":"2026032100265522100_bib10","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1038\/ng1033","article-title":"From patterns to pathways: gene expression data analysis comes of age","volume":"32","author":"Slonim","year":"2002","journal-title":"Nat Genet"},{"key":"2026032100265522100_bib11","doi-asserted-by":"crossref","first-page":"15858","DOI":"10.1073\/pnas.0707413104","article-title":"Genome-wide profiling identifies epithelial cell genes associated with asthma and with treatment response to corticosteroids","volume":"104","author":"Woodruff","year":"2007","journal-title":"Proc Natl Acad Sci USA"},{"key":"2026032100265522100_bib12","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1164\/rccm.200903-0392OC","article-title":"T-helper type 2-driven inflammation defines major subphenotypes of asthma","volume":"180","author":"Woodruff","year":"2009","journal-title":"Am J Respir Crit Care Med"},{"key":"2026032100265522100_bib13","doi-asserted-by":"crossref","first-page":"760","DOI":"10.1111\/j.1365-2222.2011.03860.x","article-title":"Nitric oxide and related enzymes in asthma: relation to severity, enzyme function and inflammation","volume":"42","author":"Yamamoto","year":"2012","journal-title":"Clin Exp Allergy"},{"key":"2026032100265522100_bib14","doi-asserted-by":"crossref","first-page":"936","DOI":"10.1111\/j.1365-2222.2008.02969.x","article-title":"IL-13 induced increases in nitrite levels are primarily driven by increases in inducible nitric oxide synthase as compared with effects on arginases in human primary bronchial epithelial cells","volume":"38","author":"Chibana","year":"2008","journal-title":"Clin Exp Allergy"},{"key":"2026032100265522100_bib15","doi-asserted-by":"crossref","first-page":"1088","DOI":"10.1056\/NEJMoa1106469","article-title":"Lebrikizumab treatment in adults with asthma","volume":"365","author":"Corren","year":"2011","journal-title":"N Engl J Med"},{"key":"2026032100265522100_bib16","doi-asserted-by":"crossref","first-page":"2455","DOI":"10.1056\/NEJMoa1304048","article-title":"Dupilumab in persistent asthma with elevated eosinophil levels","volume":"368","author":"Wenzel","year":"2013","journal-title":"N Engl J Med"},{"key":"2026032100265522100_bib17","doi-asserted-by":"crossref","first-page":"1422","DOI":"10.1016\/S0140-6736(07)61600-6","article-title":"Effect of an interleukin-4 variant on late phase asthmatic response to allergen challenge in asthmatic patients: results of two phase 2a studies","volume":"370","author":"Wenzel","year":"2007","journal-title":"Lancet"},{"key":"2026032100265522100_bib18","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1164\/rccm.200905-0695OC","article-title":"Use of exhaled nitric oxide measurement to identify a reactive, at-risk phenotype among patients with asthma","volume":"181","author":"Dweik","year":"2010","journal-title":"Am J Respir Crit Care Med"},{"key":"2026032100265522100_bib19","doi-asserted-by":"crossref","first-page":"1218","DOI":"10.1016\/j.jaci.2006.08.019","article-title":"Features of severe asthma in school-age children: atopy and increased exhaled nitric oxide","volume":"118","author":"Fitzpatrick","year":"2006","journal-title":"J Allergy Clin Immunol"},{"key":"2026032100265522100_bib20","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1164\/rccm.9120-11ST","article-title":"An official ATS clinical practice guideline: interpretation of exhaled nitric oxide levels (FENO) for clinical applications","volume":"184","author":"Dweik","year":"2011","journal-title":"Am J Respir Crit Care Med"},{"key":"2026032100265522100_bib21","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1164\/rccm.200610-1427OC","article-title":"The use of exhaled nitric oxide to guide asthma management: a randomized controlled trial","volume":"176","author":"Shaw","year":"2007","journal-title":"Am J Respir Crit Care Med"},{"key":"2026032100265522100_bib22","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1016\/j.jaci.2013.10.031","article-title":"Characterization of factors associated with systemic corticosteroid use in severe asthma: data from the Severe Asthma Research Program","volume":"133","author":"Wysocki","year":"2014","journal-title":"J Allergy Clin Immunol"},{"key":"2026032100265522100_bib23","doi-asserted-by":"crossref","DOI":"10.1016\/j.jaci.2013.12.632","article-title":"Bronchial epithelial cell gene expression in relation to exhaled nitric oxide identifies new molecular asthma phenotypes [abstract]","volume":"133","author":"Modena","year":"2014","journal-title":"J Allergy Clin Immunol"},{"key":"2026032100265522100_bib24","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1002\/(SICI)1097-0266(199606)17:6<441::AID-SMJ819>3.0.CO;2-G","article-title":"The application of cluster analysis in strategic management research: an analysis and critique","volume":"17","author":"Ketchen","year":"1996","journal-title":"Strateg Manage J"},{"key":"2026032100265522100_bib25","doi-asserted-by":"crossref","first-page":"1279","DOI":"10.1016\/j.jaci.2007.08.046","article-title":"Epithelium: at the interface of innate and adaptive immune responses","volume":"120","author":"Schleimer","year":"2007","journal-title":"J Allergy Clin Immunol"},{"key":"2026032100265522100_bib26","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1042\/bj3610537","article-title":"Heterogeneity of airways mucus: variations in the amounts and glycoforms of the major oligomeric mucins MUC5AC and MUC5B","volume":"361","author":"Kirkham","year":"2002","journal-title":"Biochem J"},{"key":"2026032100265522100_bib27","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1164\/ajrccm.163.2.2004039","article-title":"Mild and moderate asthma is associated with airway goblet cell hyperplasia and abnormalities in mucin gene expression","volume":"163","author":"Ordo\u00f1ez","year":"2001","journal-title":"Am J Respir Crit Care Med"},{"key":"2026032100265522100_bib28","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1038\/nature12807","article-title":"Muc5b is required for airway defence","volume":"505","author":"Roy","year":"2014","journal-title":"Nature"},{"key":"2026032100265522100_bib29","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1172\/JCI1378","article-title":"Nitric oxide synthesis in the lung. Regulation by oxygen through a kinetic mechanism","volume":"101","author":"Dweik","year":"1998","journal-title":"J Clin Invest"},{"key":"2026032100265522100_bib30","doi-asserted-by":"crossref","first-page":"5970","DOI":"10.4049\/jimmunol.164.11.5970","article-title":"Molecular mechanisms of increased nitric oxide (NO) in asthma: evidence for transcriptional and post-translational regulation of NO synthesis","volume":"164","author":"Guo","year":"2000","journal-title":"J Immunol"},{"key":"2026032100265522100_bib31","doi-asserted-by":"crossref","first-page":"7809","DOI":"10.1073\/pnas.92.17.7809","article-title":"Continuous nitric oxide synthesis by inducible nitric oxide synthase in normal human airway epithelium in vivo","volume":"92","author":"Guo","year":"1995","journal-title":"Proc Natl Acad Sci USA"},{"key":"2026032100265522100_bib32","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1056\/NEJM198902023200502","article-title":"Association of asthma with serum IgE levels and skin-test reactivity to allergens","volume":"320","author":"Burrows","year":"1989","journal-title":"N Engl J Med"},{"key":"2026032100265522100_bib33","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/j.jaci.2007.02.045","article-title":"Association between IgE levels and asthma severity among African American, Mexican, and Puerto Rican patients with asthma","volume":"120","author":"Naqvi","year":"2007","journal-title":"J Allergy Clin Immunol"},{"key":"2026032100265522100_bib34","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1002\/gepi.21702","article-title":"African ancestry is a risk factor for asthma and high total IgE levels in African admixed populations","volume":"37","author":"Vergara","year":"2013","journal-title":"Genet Epidemiol"},{"key":"2026032100265522100_bib35","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1016\/j.jaci.2007.05.030","article-title":"TH2 and TH1 lung inflammation induced by airway allergen sensitization with low and high doses of double-stranded RNA","volume":"120","author":"Jeon","year":"2007","journal-title":"J Allergy Clin Immunol"},{"key":"2026032100265522100_bib36","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1038\/ni.1892","article-title":"The many paths to asthma: phenotype shaped by innate and adaptive immunity","volume":"11","author":"Kim","year":"2010","journal-title":"Nat Immunol"},{"key":"2026032100265522100_bib37","doi-asserted-by":"crossref","first-page":"1175","DOI":"10.1038\/mi.2014.6","article-title":"An airway epithelial iNOS-DUOX2-thyroid peroxidase metabolome drives Th1\/Th2 nitrative stress in human severe asthma","volume":"7","author":"Voraphani","year":"2014","journal-title":"Mucosal Immunol"}],"container-title":["American Journal of Respiratory and Critical Care Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/ajrccm\/article-pdf\/190\/12\/1363\/67218071\/ajrccm_190_12_1363.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ajrccm\/article-pdf\/190\/12\/1363\/67218071\/ajrccm_190_12_1363.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,21]],"date-time":"2026-03-21T04:27:09Z","timestamp":1774067229000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ajrccm\/article\/190\/12\/1363\/8505237"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,12,1]]},"references-count":37,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2014,12,1]]},"published-print":{"date-parts":[[2014,12,15]]}},"URL":"https:\/\/doi.org\/10.1164\/rccm.201406-1099oc","relation":{},"ISSN":["1073-449X","1535-4970"],"issn-type":[{"value":"1073-449X","type":"print"},{"value":"1535-4970","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2014,12]]},"published":{"date-parts":[[2014,12,1]]}}}