Domschke Katharina, Tidow Nicola, Schwarte Kathrin, Ziegler Christiane, Lesch Klaus-Peter, Deckert Jürgen, Arolt Volker, Zwanzger Peter, Baune Bernhard T
Department of Psychiatry, University of Wuerzburg, Fuechsleinstrasse 15, 97080, Wurzburg, Germany,
J Neural Transm (Vienna). 2015 Jan;122(1):99-108. doi: 10.1007/s00702-014-1227-x. Epub 2014 May 10.
The monoamine oxidase A (MAO-A) gene has been suggested to be involved in the pathogenesis as well as the pharmacological treatment of major depressive disorder. In the present analysis, for the first time a pharmacoepigenetic approach was applied investigating the influence of DNA methylation patterns in the MAO-A regulatory and exon1/intron1 region on antidepressant treatment response. 94 patients of Caucasian descent with major depressive disorder (f = 61; DSM-IV) were analyzed for DNA methylation status at 43 MAO-A CpG sites via direct sequencing of sodium bisulfite treated DNA extracted from blood cells. Patients were also genotyped for the functional MAO-A VNTR. Clinical response to antidepressant treatment with escitalopram was assessed by intra-individual changes of HAM-D-21 scores after 6 weeks of treatment. Apart from two CpG sites, male subjects showed no or only very minor methylation. In female patients, lower methylation at two individual CpG sites in the MAO-A promoter region was nominally associated with impaired response to antidepressant treatment after 6 weeks (GRCh37/hg19: CpG 43.514.063, p = 0.04; CpG 43.514.684, p = 0.009), not, however, withstanding correction for multiple testing. MAO-A VNTR genotypes did not influence MAO-A methylation status. The present pilot data do not suggest a major influence of MAO-A DNA methylation on antidepressant treatment response. However, the presently observed trend towards CpG-specific MAO-A gene hypomethylation-possibly via increased gene expression and consecutively decreased serotonin and/or norepinephrine availability-to potentially drive impaired antidepressant treatment response in female patients might be worthwhile to be followed up in larger pharmacoepigenetic studies.
单胺氧化酶A（MAO-A）基因被认为与重度抑郁症的发病机制以及药物治疗有关。在本分析中，首次应用药物表观遗传学方法研究MAO-A调控区和外显子1/内含子1区域的DNA甲基化模式对抗抑郁治疗反应的影响。通过对从血细胞中提取的经亚硫酸氢钠处理的DNA进行直接测序，分析了94名患有重度抑郁症（f = 61；DSM-IV）的白种人患者在43个MAO-A CpG位点的DNA甲基化状态。患者还进行了功能性MAO-A VNTR基因分型。通过治疗6周后汉密尔顿抑郁量表（HAM-D-21）评分的个体内变化评估对艾司西酞普兰抗抑郁治疗的临床反应。除了两个CpG位点外，男性受试者未显示甲基化或仅有非常轻微的甲基化。在女性患者中，MAO-A启动子区域两个单独的CpG位点较低的甲基化与6周后对抗抑郁治疗的反应受损名义上相关（GRCh37/hg19：CpG 43.514.063，p = 0.04；CpG 43.514.684，p = 0.009），然而，在进行多重检验校正后并非如此。MAO-A VNTR基因型不影响MAO-A甲基化状态。目前的初步数据并不表明MAO-A DNA甲基化对抗抑郁治疗反应有重大影响。然而，目前观察到的MAO-A基因CpG特异性低甲基化趋势——可能通过增加基因表达并进而降低血清素和/或去甲肾上腺素的可用性——来潜在地导致女性患者抗抑郁治疗反应受损，这可能值得在更大规模的药物表观遗传学研究中进一步跟进。
