Table_2_Methylation of FKBP5 and SLC6A4 in Relation to Treatment Response to Mindfulness Based Stress Reduction for Posttraumatic Stress Disorder.XLSX

Mindfulness Based Stress Reduction (MBSR) is an effective non-pharmacologic treatment for veterans with PTSD. Extensive work has identified epigenetic factors related to PTSD disease risk and pathophysiology, but how these factors influence treatment response is unclear. Serotonin signaling and hypothalamic-pituitary-adrenal (HPA) axis functioning may be perturbed in PTSD and are molecular pathways targeted by PTSD treatments. To identify potential biomarkers for treatment response, we utilized genomic DNA isolated from peripheral blood samples from veterans with PTSD who were responders (n = 11) or non-responders (n = 11) to MBSR as part of a clinical trial. We assessed methylation levels at CpG sites in regions of the serotonin transporter (SLC6A4) previously associated with expression and depression outcomes, as well as the Intron 7 region of the FK506 binding protein 5 (FKBP5) containing known glucocorticoid response elements suggested to regulate this gene. Selected subjects were matched across MBSR responder status by baseline symptoms, age, sex, current smoking status, and current antidepressant use. Percent methylation was compared between responders and non-responders at baseline (pre-MBSR treatment). Additionally, percent change in methylation from baseline to post-treatment was compared between responders and non-responders. There was a significant time x responder group interaction for methylation in FKBP5 intron 7 bin 2 [F(1, 19) = 7.492, p = 0.013] whereby responders had an increase in methylation and non-responders had a decrease in methylation from before to after treatment in this region. Analyses of the three CpG sites within bin 2 revealed a significant time x responder group interaction for CpG_35558513 [F(1, 19) = 5.551, p = 0.029] which resides in a known glucocorticoid response element (GRE). Increases in FKBP5 methylation after treatment in responders as compared to decreases in non-responders suggest that effective meditation intervention may be associated with stress-related pathways at the molecular level. These preliminary findings suggest that DNA methylation signatures within FKBP5 are potential indicators of response to meditation treatment in PTSD and require validation in larger cohorts.

基于正念的压力缓解疗法（Mindfulness Based Stress Reduction，MBSR）是针对创伤后应激障碍（Post-Traumatic Stress Disorder，PTSD）退伍军人的有效非药物治疗手段。既往大量研究已明确与PTSD发病风险及病理生理学相关的表观遗传调控因子，但此类因子如何影响治疗应答仍尚不明确。血清素信号通路与下丘脑-垂体-肾上腺（hypothalamic-pituitary-adrenal，HPA）轴功能在PTSD患者中可能存在紊乱，且二者均为PTSD治疗的靶向分子通路。为鉴定潜在的治疗应答生物标志物，本研究利用一项临床试验中纳入的PTSD退伍军人的外周血样本基因组DNA，这些受试者根据对MBSR的应答情况分为应答组（n=11）与无应答组（n=11）。我们检测了既往与基因表达及抑郁转归相关的血清素转运体（serotonin transporter，SLC6A4）区域内CpG位点的甲基化水平，同时检测了FK506结合蛋白5（FK506 binding protein 5，FKBP5）内含子7区域的甲基化水平——该区域包含已知的糖皮质激素反应元件，被认为可调控该基因的表达。所选受试者根据MBSR应答状态，在基线症状、年龄、性别、当前吸烟状态及当前抗抑郁药使用情况方面进行了匹配。我们对比了两组受试者在基线（MBSR治疗前）时的甲基化百分比水平。此外，还对比了两组受试者从基线至治疗后甲基化水平的变化百分比。FKBP5内含子7 bin 2区域的甲基化水平存在显著的时间×应答组交互效应[F(1, 19)=7.492, p=0.013]，具体表现为：从治疗前至治疗后，应答组该区域的甲基化水平升高，而无应答组则出现降低。对bin 2区域内3个CpG位点的分析显示，CpG_35558513位点存在显著的时间×应答组交互效应[F(1, 19)=5.551, p=0.029]，该位点位于已知的糖皮质激素反应元件（glucocorticoid response element，GRE）内。相较于无应答组的甲基化水平降低，应答组在治疗后FKBP5甲基化水平升高，这提示有效的正念冥想干预可能在分子层面与应激相关通路存在关联。本初步研究结果表明，FKBP5基因内的DNA甲基化特征可作为PTSD患者对冥想治疗应答的潜在预测指标，后续需在更大规模的队列中进行验证。