Profiling of genes expressed in peripheral blood mononuclear cells predicts glucocorticoid sensitivity in asthma patients

2.50
Hdl Handle:
http://hdl.handle.net/2336/57933
Title:
Profiling of genes expressed in peripheral blood mononuclear cells predicts glucocorticoid sensitivity in asthma patients
Authors:
Hakonarson, Hakon; Bjornsdottir, Unnur S; Halapi, Eva; Bradfield, Jonathan; Zink, Florian; Mouy, Magali; Helgadottir, Hildur; Gudmundsdottir, Asta S; Andrason, Hjalti; Adalsteinsdottir, Asdis E; Kristjansson, Kristleifur; Birkisson, Illugi; Arnason, Thor; Andresdottir, Margret; Gislason, David; Gislason, Thorarinn; Gulcher, Jeffrey R; Stefansson, Kari
Citation:
Proc. Natl. Acad. Sci. U.S.A.. 2005, 102(41):14789-94
Issue Date:
11-Oct-2005
Abstract:
Gene expression profiles were examined in freshly isolated peripheral blood mononuclear cells (PBMC) from two independent cohorts (training and test sets) of glucocorticoid (GC)-sensitive (n = 64) and GC-resistant (n = 42) asthma patients in search of genes that accurately predict responders and nonresponders to inhaled corticosteroids. A total of 11,812 genes were examined with high-density oligonucleotide microarrays in both resting PBMC (106 patients) and cells treated in vitro with IL-1beta and TNF-alpha combined (88 patients), with or without GC. A total of 5,011 genes were expressed at significant levels in the PBMC, and 1,334 of those were notably up-regulated or down-regulated by IL-1beta/TNF-alpha treatment. The expression changes of 923 genes were significantly reversed in GC responders in the presence of GC. The expression pattern of 15 of these 923 genes that most accurately separated GC responders (n = 26) from the nonresponders (n = 18) in the training set, based on the weighted voting algorithm, predicted the independent test set of equal size with 84% accuracy. The expression accuracy of these genes was confirmed by real-time-quantitative PCR, wherein 11 of the 15 genes predicted GC sensitivity at baseline with 84% accuracy, with one gene predicting at 81% in an independent cohort of 79 patients. We conclude that we have uncovered gene expression profiles in PBMC that predict clinical response to inhaled GC therapy with meaningful accuracy. Upon validation in an independent study, these results support the development of a diagnostic test to guide GC therapy in asthma patients.
Description:
To access publisher full text version of this article. Please click on the hyperlink in Additional Links field
Additional Links:
http://dx.doi.org/10.1073/pnas.0409904102

Full metadata record

DC FieldValue Language
dc.contributor.authorHakonarson, Hakon-
dc.contributor.authorBjornsdottir, Unnur S-
dc.contributor.authorHalapi, Eva-
dc.contributor.authorBradfield, Jonathan-
dc.contributor.authorZink, Florian-
dc.contributor.authorMouy, Magali-
dc.contributor.authorHelgadottir, Hildur-
dc.contributor.authorGudmundsdottir, Asta S-
dc.contributor.authorAndrason, Hjalti-
dc.contributor.authorAdalsteinsdottir, Asdis E-
dc.contributor.authorKristjansson, Kristleifur-
dc.contributor.authorBirkisson, Illugi-
dc.contributor.authorArnason, Thor-
dc.contributor.authorAndresdottir, Margret-
dc.contributor.authorGislason, David-
dc.contributor.authorGislason, Thorarinn-
dc.contributor.authorGulcher, Jeffrey R-
dc.contributor.authorStefansson, Kari-
dc.date.accessioned2009-03-30T15:28:11Z-
dc.date.available2009-03-30T15:28:11Z-
dc.date.issued2005-10-11-
dc.date.submitted2009-03-30-
dc.identifier.citationProc. Natl. Acad. Sci. U.S.A.. 2005, 102(41):14789-94en
dc.identifier.issn0027-8424-
dc.identifier.pmid16203992-
dc.identifier.doi10.1073/pnas.0409904102-
dc.identifier.urihttp://hdl.handle.net/2336/57933-
dc.descriptionTo access publisher full text version of this article. Please click on the hyperlink in Additional Links fielden
dc.description.abstractGene expression profiles were examined in freshly isolated peripheral blood mononuclear cells (PBMC) from two independent cohorts (training and test sets) of glucocorticoid (GC)-sensitive (n = 64) and GC-resistant (n = 42) asthma patients in search of genes that accurately predict responders and nonresponders to inhaled corticosteroids. A total of 11,812 genes were examined with high-density oligonucleotide microarrays in both resting PBMC (106 patients) and cells treated in vitro with IL-1beta and TNF-alpha combined (88 patients), with or without GC. A total of 5,011 genes were expressed at significant levels in the PBMC, and 1,334 of those were notably up-regulated or down-regulated by IL-1beta/TNF-alpha treatment. The expression changes of 923 genes were significantly reversed in GC responders in the presence of GC. The expression pattern of 15 of these 923 genes that most accurately separated GC responders (n = 26) from the nonresponders (n = 18) in the training set, based on the weighted voting algorithm, predicted the independent test set of equal size with 84% accuracy. The expression accuracy of these genes was confirmed by real-time-quantitative PCR, wherein 11 of the 15 genes predicted GC sensitivity at baseline with 84% accuracy, with one gene predicting at 81% in an independent cohort of 79 patients. We conclude that we have uncovered gene expression profiles in PBMC that predict clinical response to inhaled GC therapy with meaningful accuracy. Upon validation in an independent study, these results support the development of a diagnostic test to guide GC therapy in asthma patients.en
dc.language.isoenen
dc.publisherNational Academy of Sciencesen
dc.relation.urlhttp://dx.doi.org/10.1073/pnas.0409904102en
dc.subject.meshAdulten
dc.subject.meshAgeden
dc.subject.meshAsthmaen
dc.subject.meshCohort Studiesen
dc.subject.meshFemaleen
dc.subject.meshGene Expression Profilingen
dc.subject.meshGene Expression Regulationen
dc.subject.meshGlucocorticoidsen
dc.subject.meshHumansen
dc.subject.meshIcelanden
dc.subject.meshInterleukin-1en
dc.subject.meshLeukocytes, Mononuclearen
dc.subject.meshMaleen
dc.subject.meshMiddle Ageden
dc.subject.meshOligonucleotide Array Sequence Analysisen
dc.subject.meshReverse Transcriptase Polymerase Chain Reactionen
dc.subject.meshTumor Necrosis Factor-alphaen
dc.titleProfiling of genes expressed in peripheral blood mononuclear cells predicts glucocorticoid sensitivity in asthma patientsen
dc.typeArticleen
dc.contributor.departmentdeCODE genetics, Inc., Sturlugata 8, IS-101 Reykjavik, Iceland. hakonh@decode.isen
dc.identifier.journalProceedings of the National Academy of Sciences of the United States of Americaen

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