Transcriptional signatures related to glucose and lipid metabolism predict treatment response to the tumor necrosis factor antagonist infliximab in patients with treatment-resistant depression.
Transcriptional signatures related to glucose and lipid metabolism predict treatment response to the tumor necrosis factor antagonist infliximab in patients with treatment-resistant depression.
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DOI：
10.1016/j.bbi.2013.04.004
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发表时间：
2013-07
影响因子：
15.1
通讯作者：
Felger, Jennifer C.
中科院分区：
文献类型：
--
作者：
Mehta, Divya;Raison, Charles L.;Woolwine, Bobbi J.;Haroon, Ebrahim;Binder, Elisabeth B.;Miller, Andrew H.;Felger, Jennifer C.
最近发现肿瘤坏死因子（TNF）拮抗剂英夫利西单抗可减轻基线炎症增加（反映为血浆C反应蛋白浓度> 5 mg/L）患者的抑郁症状。为了进一步探索对英夫利西单抗应答的预测因子和靶点，在基线和首次英夫利西单抗输注后6小时、24小时和2周，与安慰剂相比，检测了来自英夫利西单抗应答者（n=13）与非应答者（n=14）的外周血单核细胞中的差异基因表达。治疗反应被定义为在12周试验期间的任何时间点抑郁症状减少50%。148个基因转录物与英夫利西单抗应答显著相关（1.2倍，调整后p≤0.01），与安慰剂应答者不同。预测英夫利西单抗应答的转录本与肝细胞生成和胆固醇转运相关，并在受肝细胞核因子（HNF）4-α（一种参与肝细胞生成和胆固醇及脂质稳态的转录因子）调节的网络中富集。在基线时差异表达的148个转录物中，48%在英夫利西单抗应答者中随时间显著调节，包括与肿瘤发生和HNF 4-α网络相关的基因，表明这些预测基因对英夫利西单抗有应答。在输注后6小时和24小时，应答者还表现出通过TNF信号传导抑制与细胞凋亡相关的基因。英夫利西单抗治疗2周后应答者转录下调与先天免疫信号传导和核因子-κ B相关。因此，反映葡萄糖和脂质代谢改变的基线转录特征预测了英夫利西单抗的抗抑郁反应，英夫利西单抗的反应涉及代谢基因的调节和先天免疫激活相关基因的抑制。
The tumor necrosis factor (TNF) antagonist infliximab was recently found to reduce depressive symptoms in patients with increased baseline inflammation as reflected by a plasma C-reactive protein concentration >5mg/L. To further explore predictors and targets of response to infliximab, differential gene expression was examined in peripheral blood mononuclear cells from infliximab responders (n=13) versus non-responders (n=14) compared to placebo at baseline and 6hr, 24hr, and 2 weeks after the first infliximab infusion. Treatment response was defined as 50% reduction in depressive symptoms at any point during the 12-week trial. One-hundred-forty-eight gene transcripts were significantly associated (1.2 fold, adjusted p≤0.01) with response to infliximab and were distinct from placebo responders. Transcripts predictive of infliximab response were associated with gluconeogenesis and cholesterol transport, and were enriched in a network regulated by hepatocyte nuclear factor (HNF)4-alpha, a transcription factor involved in gluconeogenesis and cholesterol and lipid homeostasis. Of the 148 transcripts differentially expressed at baseline, 48% were significantly regulated over time in infliximab responders, including genes related to gluconeogenesis and the HNF4-alpha network, indicating that these predictive genes were responsive to infliximab. Responders also demonstrated inhibition of genes related to apoptosis through TNF signaling at 6hr and 24hr after infusion. Transcripts down-regulated in responders 2 weeks after infliximab were related to innate immune signaling and nuclear factor-kappa B. Thus, baseline transcriptional signatures reflective of alterations in glucose and lipid metabolism predicted antidepressant response to infliximab, and infliximab response involved regulation of metabolic genes and inhibition of genes related to innate immune activation.
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影响因子：
7.4
作者：
Felger JC;Miller AH
通讯作者：
Miller AH
影响因子：
10.6
作者：
Dowlati, Yekta;Herrmann, Nathan;Lanctot, Krista L.
通讯作者：
Lanctot, Krista L.
影响因子：
6.5
作者：
Haider, Asifa S.;Cohen, Jules;Krueger, James G.
通讯作者：
Krueger, James G.
影响因子：
10.6
作者：
Harrison NA;Brydon L;Walker C;Gray MA;Steptoe A;Critchley HD
通讯作者：
Critchley HD
影响因子：
7.6
作者：
Godbout, Jonathan P.;Moreau, Maite;Johnson, Rodney W.
通讯作者：
Johnson, Rodney W.