Department of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Germany.
Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Würzburg, Germany.
Int J Neuropsychopharmacol. 2018 May 1;21(5):423-432. doi: 10.1093/ijnp/pyx111.
Posttraumatic stress disorder is characterized by an overactive noradrenergic system conferring core posttraumatic stress disorder symptoms such as hyperarousal and reexperiencing. Monoamine oxidase A is one of the key enzymes mediating the turnover of noradrenaline. Here, DNA methylation of the monoamine oxidase A gene exonI/intronI region was investigated for the first time regarding its role in posttraumatic stress disorder risk and severity.
Monoamine oxidase A methylation was analyzed via direct sequencing of sodium bisulfite-treated DNA extracted from blood cells in a total sample of N=652 (441 male) patients with current posttraumatic stress disorder, patients with remitted posttraumatic stress disorder, and healthy probands (comparison group) recruited at 5 centers in Bosnia-Herzegovina, Croatia, and the Republic of Kosovo. Posttraumatic stress disorder severity was measured by means of the Clinician-Administered Posttraumatic Stress Disorder Scale and its respective subscores representing distinct symptom clusters.
In the male, but not the female sample, patients with current posttraumatic stress disorder displayed hypermethylation of 3 CpGs (CpG3=43656362; CpG12=43656514; CpG13=43656553, GRCh38.p2 Assembly) as compared with remitted Posttraumatic Stress Disorder patients and healthy probands. Symptom severity (Clinician-Administered Posttraumatic Stress Disorder Scale scores) in male patients with current posttraumatic stress disorder significantly correlated with monoamine oxidase A methylation. This applied particularly to symptom clusters related to reexperiencing of trauma (cluster B) and hyperarousal (cluster D).
The present findings suggest monoamine oxidase A gene hypermethylation, potentially resulting in enhanced noradrenergic signalling, as a disease status and severity marker of current posttraumatic stress disorder in males. If replicated, monoamine oxidase A hypermethylation might serve as a surrogate marker of a hyperadrenergic subtype of posttraumatic stress disorder guiding personalized treatment decisions on the use of antiadrenergic agents.
创伤后应激障碍的特征是去甲肾上腺素能系统过度活跃，从而导致核心创伤后应激障碍症状，如过度警觉和再体验。单胺氧化酶 A 是介导去甲肾上腺素周转率的关键酶之一。在这里，首次研究了单胺氧化酶 A 基因外显子 I/内含子 I 区域的 DNA 甲基化在创伤后应激障碍风险和严重程度中的作用。
通过对来自波斯尼亚和黑塞哥维那、克罗地亚和科索沃共和国 5 个中心招募的 652 名（441 名男性）当前创伤后应激障碍患者、缓解期创伤后应激障碍患者和健康对照者的血细胞中提取的经亚硫酸氢盐处理的 DNA 进行直接测序，分析单胺氧化酶 A 的甲基化。创伤后应激障碍严重程度采用临床医生管理创伤后应激障碍量表及其代表不同症状群的各自亚量表进行测量。
在男性样本中，但在女性样本中，当前创伤后应激障碍患者的 3 个 CpG（CpG3=43656362；CpG12=43656514；CpG13=43656553，GRCh38.p2 组装）表现出超甲基化，与缓解期创伤后应激障碍患者和健康对照者相比。当前创伤后应激障碍男性患者的症状严重程度（临床医生管理创伤后应激障碍量表评分）与单胺氧化酶 A 甲基化显著相关。这尤其适用于与创伤再体验（集群 B）和过度警觉（集群 D）相关的症状集群。
本研究结果表明，单胺氧化酶 A 基因超甲基化可能导致去甲肾上腺素能信号增强，作为男性当前创伤后应激障碍的疾病状态和严重程度标志物。如果得到复制，单胺氧化酶 A 超甲基化可能作为创伤后应激障碍去甲肾上腺素能亚型的替代标志物，指导抗去甲肾上腺素能药物的个体化治疗决策。
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