Increased ratio of anti-apoptotic to pro-apoptotic Bcl2 gene-family members in lithium-responders one month after treatment initiation.
Increased ratio of anti-apoptotic to pro-apoptotic Bcl2 gene-family members in lithium-responders one month after treatment initiation.
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DOI：
10.1186/2045-5380-2-15
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发表时间：
2012-09-12
期刊：
影响因子：
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通讯作者：
Beech R
中科院分区：
文献类型：
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作者：
Lowthert L;Leffert J;Lin A;Umlauf S;Maloney K;Muralidharan A;Lorberg B;Mane S;Zhao H;Sinha R;Bhagwagar Z;Beech R
锂被许多人认为是双相情感障碍（BD）管理的金标准药物。然而，锂的临床反应是异质性的，这种反应差异的分子基础尚不清楚。在本研究中，我们试图确定双相情感障碍（BD）患者的外周血基因表达谱如何随着锂治疗的开始而变化，以及这些基因表达谱随时间的差异是否与临床反应有关。使用含有> 48，000个转录物探针的Illumina Sentrix Beadchip（Human-6v 2）微阵列来测量来自20名患有BD的抑郁受试者的外周血中的基因表达的表达水平，所述受试者在用锂进行开放标签治疗的8周之前和期间每两周进行一次。比较治疗应答者（定义为汉密尔顿抑郁量表降低50%或更多）和无应答者之间基因表达的变化。使用GeneGO Metacore软件进行通路分析。127个基因在应答者与非应答者中显示出差异应答。通路分析表明，这些基因中，细胞凋亡的调控是最显着的影响途径。对BCL 2相关基因之间变化的时间过程的更仔细检查显示，在锂应答者中，在开始用锂治疗后一个月，包括Bcl 2和胰岛素受体底物2（IRS 2）的几个抗凋亡基因上调，而促凋亡基因，包括BCL 2拮抗剂/杀伤剂1（BAK 1）和BCL 2相关的细胞死亡激动剂（BAD）下调。相比之下，在锂无应答者中，BCL 2和IRS 2在一个月的时间点下调，而BAK 1和BAD在一个月的时间点上调。这些结果表明，锂治疗后促凋亡和抗凋亡基因表达平衡的差异性变化可能解释BD患者临床反应的某些异质性。
Lithium is considered by many as the gold standard medication in the management of bipolar disorder (BD). However, the clinical response to lithium is heterogeneous, and the molecular basis for this difference in response is unknown. In the present study, we sought to determine how the peripheral blood gene expression profiles of patients with bipolar disorder (BD) changed over time following intitiation of treatment with lithium, and whether differences in those profiles over time were related to the clinical response. Illumina Sentrix Beadchip (Human-6v2) microarrays containing > 48,000 transcript probes were used to measure levels of expression of gene-expression in peripheral blood from 20 depressed subjects with BD prior to and every two weeks during 8 weeks of open-label treatment with lithium. Changes in gene-expression were compared between treatment responders (defined as a decrease in the Hamilton Depression Rating Scale of 50% or more) and non-responders. Pathway analysis was conducted using GeneGO Metacore software. 127 genes showed a differential response in responders vs. non-responders. Pathway analysis showed that regulation of apoptosis was the most significantly affected pathway among these genes. Closer examination of the time-course of changes among BCL2 related genes showed that in lithium-responders, one month after starting treatment with lithium, several anti-apoptotic genes including Bcl2 and insulin receptor substrate 2 (IRS2) were up-regulated, while pro-apoptotic genes, including BCL2-antagonist/killer 1 (BAK1) and BCL2-associated agonist of cell death (BAD), were down-regulated. In contrast, in lithium non-responders, BCL2 and IRS2 were down-regulated, while BAK1 and BAD up-regulated at the one-month time-point. These results suggest that differential changes in the balance of pro- and anti- apoptotic gene-expression following treatment with lithium may explain some of the heterogeneity in clinical response in BD patients.