Department of Biomedical Sciences, University of Teramo, Teramo, Italy.
Neuropsychopharmacology. 2012 Jun;37(7):1647-55. doi: 10.1038/npp.2012.10. Epub 2012 Feb 22.
The etiology of bipolar disorder (BD) is still poorly understood, involving genetic and epigenetic mechanisms as well as environmental contributions. This study aimed to investigate the degree of DNA methylation at the promoter region of the brain-derived neurotrophic factor (BDNF) gene, as one of the candidate genes associated with major psychoses, in peripheral blood mononuclear cells isolated from 94 patients with BD (BD I=49, BD II=45) and 52 healthy controls. A significant BDNF gene expression downregulation was observed in BD II 0.53±0.11%; P<0.05), but not in BD I (1.13±0.19%) patients compared with controls (CONT: 1±0.2%). Consistently, an hypermethylation of the BDNF promoter region was specifically found in BD II patients (CONT: 24.0±2.1%; BDI: 20.4±1.7%; BDII: 33.3±3.5%, P<0.05). Of note, higher levels of DNA methylation were observed in BD subjects on pharmacological treatment with mood stabilizers plus antidepressants (34.6±4.2%, predominantly BD II) compared with those exclusively on mood-stabilizing agents (21.7±1.8%; P<0.01, predominantly BD I). Moreover, among the different pharmacological therapies, lithium (20.1±3.8%, P<0.05) and valproate (23.6±2.9%, P<0.05) were associated with a significant reduction of DNA methylation compared with other drugs (35.6±4.6%). Present findings suggest selective changes in DNA methylation of BDNF promoter in subjects with BD type II and highlight the importance of epigenetic factors in mediating the onset and/or susceptibility to BD, providing new insight into the mechanisms of gene expression. Moreover, they shed light on possible mechanisms of action of mood-stabilizing compounds vs antidepressants in the treatment of BD, pointing out that BDNF regulation might be a key target for their effects.
双相障碍（BD）的病因仍知之甚少，涉及遗传和表观遗传机制以及环境因素。本研究旨在探讨脑源性神经营养因子（BDNF）基因启动子区域的 DNA 甲基化程度，BDNF 是与主要精神病相关的候选基因之一，研究对象为外周血单个核细胞，共纳入 94 例 BD 患者（BD I=49，BD II=45）和 52 例健康对照者。与对照组（CONT：1±0.2%）相比，BD II 患者（0.53±0.11%；P<0.05）的 BDNF 基因表达明显下调，但在 BD I 患者中未观察到（1.13±0.19%）。同样，BD II 患者的 BDNF 启动子区域表现出特异性的高甲基化（CONT：24.0±2.1%；BDI：20.4±1.7%；BDII：33.3±3.5%；P<0.05）。值得注意的是，接受心境稳定剂联合抗抑郁药治疗的 BD 患者（主要是 BD II 患者）的 DNA 甲基化水平高于仅接受心境稳定剂治疗的患者（21.7±1.8%；P<0.01，主要是 BD I 患者）。此外，在不同的药物治疗中，与其他药物相比，锂（20.1±3.8%；P<0.05）和丙戊酸（23.6±2.9%；P<0.05）可显著降低 BDNF 启动子的 DNA 甲基化。这些发现表明，BD Ⅱ型患者 BDNF 启动子的 DNA 甲基化存在选择性变化，提示表观遗传因素在调节 BD 的发病和/或易感性方面的重要性，为基因表达机制提供了新的见解。此外，这些发现还揭示了心境稳定剂化合物与抗抑郁药治疗 BD 的可能作用机制，指出 BDNF 调节可能是它们作用的关键靶点。
