Traumatic Stress Studies Division, Department of Psychiatry, Icahn School of Medicine at Mount Sinai , New York, NY , USA ; Mental Health Care Center, PTSD Clinical Research Program and Laboratory of Clinical Neuroendocrinology and Neurochemistry, James J. Peters Veterans Affairs Medical Center , Bronx, NY , USA ; Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai , New York, NY , USA.
Front Psychiatry. 2013 Sep 27;4:118. doi: 10.3389/fpsyt.2013.00118. eCollection 2013.
Epigenetic alterations offer promise as diagnostic or prognostic markers, but it is not known whether these measures associate with, or predict, clinical state. These questions were addressed in a pilot study with combat veterans with PTSD to determine whether cytosine methylation in promoter regions of the glucocorticoid related NR3C1 and FKBP51 genes would predict or associate with treatment outcome. Veterans with PTSD received prolonged exposure (PE) psychotherapy, yielding responders (n = 8), defined by no longer meeting diagnostic criteria for PTSD, and non-responders (n = 8). Blood samples were obtained at pre-treatment, after 12 weeks of psychotherapy (post-treatment), and after a 3-month follow-up. Methylation was examined in DNA extracted from lymphocytes. Measures reflecting glucocorticoid receptor (GR) activity were also obtained (i.e., plasma and 24 h-urinary cortisol, plasma ACTH, lymphocyte lysozyme IC50-DEX, and plasma neuropeptide-Y). Methylation of the GR gene (NR3C1) exon 1F promoter assessed at pre-treatment predicted treatment outcome, but was not significantly altered in responders or non-responders at post-treatment or follow-up. In contrast, methylation of the FKBP5 gene (FKBP51) exon 1 promoter region did not predict treatment response, but decreased in association with recovery. In a subset, a corresponding group difference in FKBP5 gene expression was observed, with responders showing higher gene expression at post-treatment than non-responders. Endocrine markers were also associated with the epigenetic markers. These preliminary observations require replication and validation. However, the results support research indicating that some glucocorticoid related genes are subject to environmental regulation throughout life. Moreover, psychotherapy constitutes a form of "environmental regulation" that may alter epigenetic state. Finally, the results further suggest that different genes may be associated with prognosis and symptom state, respectively.
表观遗传改变可作为诊断或预后标志物，但尚不清楚这些指标是否与临床状态相关或可预测临床状态。本研究通过 PTSD 退伍军人的试点研究来解决这些问题，以确定糖皮质激素相关 NR3C1 和 FKBP51 基因启动子区域的胞嘧啶甲基化是否可以预测或与治疗结果相关。 PTSD 退伍军人接受了延长暴露（PE）心理治疗，产生了应答者（n=8），其标准为不再符合 PTSD 的诊断标准，而非应答者（n=8）。在治疗前、心理治疗 12 周后（治疗后）和 3 个月随访时采集血液样本。从淋巴细胞中提取 DNA 后检测甲基化。还获得了反映糖皮质激素受体（GR）活性的指标（即血浆和 24 小时尿液皮质醇、血浆 ACTH、淋巴细胞溶菌酶 IC50-DEX 和血浆神经肽-Y）。在治疗前评估的 GR 基因（NR3C1）外显子 1F 启动子的甲基化可预测治疗结果，但在治疗后或随访时应答者或非应答者均无明显变化。相比之下，FKBP5 基因（FKBP51）外显子 1 启动子区域的甲基化不能预测治疗反应，但与恢复相关而减少。在亚组中，还观察到 FKBP5 基因表达的相应组间差异，即治疗后应答者的基因表达高于非应答者。内分泌标志物也与表观遗传标志物相关。这些初步观察结果需要复制和验证。然而，结果支持表明某些糖皮质激素相关基因在整个生命周期中都受到环境调控的研究。此外，心理治疗构成了一种“环境调节”形式，可能会改变表观遗传状态。最后，结果还进一步表明，不同的基因可能分别与预后和症状状态相关。
