Domschke Katharina, Tidow Nicola, Schwarte Kathrin, Deckert Jürgen, Lesch Klaus-Peter, Arolt Volker, Zwanzger Peter, Baune Bernhard T
Department of Psychiatry, Psychosomatics and Psychotherapy,University of Wuerzburg,Germany.
Department of Psychiatry and Psychotherapy,University of Muenster,Germany.
Int J Neuropsychopharmacol. 2014 Aug;17(8):1167-76. doi: 10.1017/S146114571400039X. Epub 2014 Mar 28.
Variation in the serotonin transporter gene (5-HTT; SERT; SLC6A4) has been suggested to pharmacogenetically drive interindividual differences in antidepressant treatment response. In the present analysis, a 'pharmaco-epigenetic' approach was applied by investigating the influence of DNA methylation patterns in the 5-HTT transcriptional control region on antidepressant treatment response. Ninety-four patients of Caucasian descent with major depressive disorder (MDD) (f = 61) were analysed for DNA methylation status at nine CpG sites in the 5-HTT transcriptional control region upstream of exon 1A via direct sequencing of sodium bisulfite treated DNA extracted from blood cells. Patients were also genotyped for the functional 5-HTTLPR/rs25531 polymorphisms. Clinical response to treatment with escitalopram was assessed by intra-individual changes of HAM-D-21 scores after 6 wk of treatment. Lower average 5-HTT methylation across all nine CpGs was found to be associated with impaired antidepressant treatment response after 6 wk (p = 0.005). This effect was particularly conferred by one individual 5-HTT CpG site (CpG2 (GRCh37 build, NC_000017.10 28.563.102; p = 0.002). 5-HTTLPR/rs25531 haplotype was neither associated with 5-HTT DNA methylation nor treatment response. This analysis suggests that DNA hypomethylation of the 5-HTT transcriptional control region - possibly via increased serotonin transporter expression and consecutively decreased serotonin availability - might impair antidepressant treatment response in Caucasian patients with MDD. This pharmaco-epigenetic approach could eventually aid in establishing epigenetic biomarkers of treatment response and thereby a more personalized treatment of MDD.
血清素转运体基因（5-HTT；SERT；SLC6A4）的变异被认为可通过药物遗传学驱动个体间抗抑郁治疗反应的差异。在本分析中，采用了一种“药物表观遗传学”方法，研究5-HTT转录控制区域的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（MDD）的白种人患者（女性=61名）5-HTT转录控制区域外显子1A上游9个CpG位点的DNA甲基化状态。患者还进行了功能性5-HTTLPR/rs25531多态性基因分型。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治疗的临床反应。发现在所有9个CpG位点上较低的平均5-HTT甲基化与6周后抗抑郁治疗反应受损相关（p = 0.005）。这种效应尤其由一个单独的5-HTT CpG位点（CpG2（GRCh37版本，NC_000017.10 28.563.102；p = 0.002））所致。5-HTTLPR/rs25531单倍型既与5-HTT DNA甲基化无关，也与治疗反应无关。该分析表明，5-HTT转录控制区域的DNA低甲基化——可能通过增加血清素转运体表达并继而降低血清素可用性——可能损害白种人MDD患者的抗抑郁治疗反应。这种药物表观遗传学方法最终可能有助于建立治疗反应的表观遗传生物标志物，从而实现对MDD更个性化的治疗。
