Dexamethasone Stimulated Gene Expression in Peripheral Blood is a Sensitive Marker for Glucocorticoid Receptor Resistance in Depressed Patients
Dexamethasone Stimulated Gene Expression in Peripheral Blood is a Sensitive Marker for Glucocorticoid Receptor Resistance in Depressed Patients
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DOI：
10.1038/npp.2011.331
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发表时间：
2012-05-01
影响因子：
7.6
通讯作者：
Binder, Elisabeth B.
中科院分区：
文献类型：
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作者：
Menke, Andreas;Arloth, Janine;Binder, Elisabeth B.
尽管重性抑郁症患者外周血中的基因表达谱不太可能识别与情感性障碍的病理机制直接相关的基因，但它们可能作为这种疾病的生物标志物。由于先前使用基线基因表达谱的研究提供了不同的结果，因此我们的方法是使用体内地塞米松激发试验，并比较抑郁症患者和健康对照组之间糖皮质激素受体（GR）介导的基因表达变化。分析来自两个独立队列的全基因组基因表达数据（基线和1.5 mg地塞米松p.o刺激gr后），通过训练（N = 18例/18例对照）和测试队列（N = 11/13）确定预测病例和对照状态的基因表达模式。地塞米松导致对照组2670个基因和病例1151个转录物的可重复性调节。包括FKBP5和DUSP1在内的几个基因，先前与重度抑郁症的病理生理相关，被发现是gr激活的可靠标记。使用随机森林分析进行分类，gr刺激的基因表达优于基线基因表达作为病例和对照状态的分类器，在测试队列中正确分类率为79.1比41.6%。当使用一组精制的19个基因时，gr刺激的基因表达在地塞米松非抑制患者中表现最佳（88.7%正确分类，敏感性100%），但在抑制患者中也正确分类77.3%（敏感性76.7%）。我们的研究表明，外周血细胞中受刺激的基因表达可能是抑郁症患者体内gr功能改变的一个有希望的分子标志物，而gr功能是潜在病理的一个重要组成部分。神经精神药理学（2012）37,1455-1464；doi: 10.1038 / npp.2011.331;2012年1月11日在线发布
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. Neuropsychopharmacology (2012) 37, 1455-1464; doi: 10.1038/npp.2011.331; published online 11 January 2012