Menke, A.* ; Knauer-Arloth, J.* ; Pütz, B.* ; Weber, P.* ; Klengel, T.* ; Mehta, D.* ; Gonik, M.* ; Rex-Haffner, M.* ; Rubel, J.* ; Uhr, M.* ; Lucae, S.* ; Deussing, J.M. ; Müller-Myhsok, B.* ; Holsboer, F.* ; Binder, E.B.*
Dexamethasone stimulated gene expression in peripheral blood is a sensitive marker for glucocorticoid receptor resistance in depressed patients.
Neuropsychopharmacology 37, 1455-1464 (2012)
Although gene expression profiles in peripheral blood in major depression are not likely to identify genes directly involved in the pathomechanism of affective disorders, they may serve as biomarkers for this disorder. As previous studies using baseline gene expression profiles have provided mixed results, our approach was to use an in vivo dexamethasone challenge test and to compare glucocorticoid receptor (GR)-mediated changes in gene expression between depressed patients and healthy controls. Whole genome gene expression data (baseline and following GR-stimulation with 1.5 mg dexamethasone p.o.) from two independent cohorts were analyzed to identify gene expression pattern that would predict case and control status using a training (N=18 cases/18 controls) and a test cohort (N=11/13). Dexamethasone led to reproducible regulation of 2670 genes in controls and 1151 transcripts in cases. Several genes, including FKBP5 and DUSP1, previously associated with the pathophysiology of major depression, were found to be reliable markers of GR-activation. Using random forest analyses for classification, GR-stimulated gene expression outperformed baseline gene expression as a classifier for case and control status with a correct classification of 79.1 vs 41.6% in the test cohort. GR-stimulated gene expression performed best in dexamethasone non-suppressor patients (88.7% correctly classified with 100% sensitivity), but also correctly classified 77.3% of the suppressor patients (76.7% sensitivity), when using a refined set of 19 genes. Our study suggests that in vivo stimulated gene expression in peripheral blood cells could be a promising molecular marker of altered GR-functioning, an important component of the underlying pathology, in patients suffering from depressive episodes.
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Publikationstyp
Artikel: Journalartikel
Dokumenttyp
Wissenschaftlicher Artikel
Typ der Hochschulschrift
Herausgeber
Schlagwörter
dexamethasone; FKBP5; gene-expression; glucocorticoid receptor; major depression; RNA; POSTTRAUMATIC-STRESS-DISORDER; MEMBRANE STEROID TRANSPORTERS; FUNCTION IN-VITRO; MAJOR DEPRESSION; SUPPRESSION TEST; MESSENGER-RNA; ANTIDEPRESSANT; PROFILES; CELLS; BRAIN
Keywords plus
Sprache
englisch
Veröffentlichungsjahr
2012
Prepublished im Jahr
HGF-Berichtsjahr
2012
ISSN (print) / ISBN
0893-133X
e-ISSN
1470-634X
ISBN
Bandtitel
Konferenztitel
Konferzenzdatum
Konferenzort
Konferenzband
Quellenangaben
Band: 37,
Heft: 6,
Seiten: 1455-1464
Artikelnummer: ,
Supplement: ,
Reihe
Verlag
Nature Publishing Group
Verlagsort
Tag d. mündl. Prüfung
0000-00-00
Betreuer
Gutachter
Prüfer
Topic
Hochschule
Hochschulort
Fakultät
Veröffentlichungsdatum
0000-00-00
Anmeldedatum
0000-00-00
Anmelder/Inhaber
weitere Inhaber
Anmeldeland
Priorität
Begutachtungsstatus
Peer reviewed
POF Topic(s)
30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
30204 - Cell Programming and Repair
Forschungsfeld(er)
Genetics and Epidemiology
PSP-Element(e)
G-520600-001
G-500500-001
Förderungen
Copyright
Erfassungsdatum
2012-06-13