Gassó Patricia, Rodríguez Natalia, Boloc Daniel, Blázquez Ana, Torres Teresa, Gortat Ana, Plana Maria Teresa, Lafuente Amalia, Mas Sergi, Arnaiz Joan Albert, Lázaro Luisa
Department of Basic Clinical Practice, Unit of Pharmacology, University of Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
Department of Basic Clinical Practice, Unit of Pharmacology, University of Barcelona, Spain.
Prog Neuropsychopharmacol Biol Psychiatry. 2017 Jul 3;77:236-240. doi: 10.1016/j.pnpbp.2017.04.031. Epub 2017 Apr 26.
Genetic variability related to the brain serotonergic system has a significant impact on both the susceptibility to psychiatric disorders, such as major depressive disorder (MDD), and the response to antidepressant drugs, such as fluoxetine. TPH2 is one of the most important serotonergic candidate genes in selective serotonin reuptake inhibitors (SSRIs) pharmacogenetic studies. The aim of the present study was to evaluate the influence of regulatory polymorphisms that are specifically located in human TPH2 transcription factor binding sites (TFBSs), and therefore could be functional by altering gene expression, on clinical improvement in children and adolescents treated with fluoxetine. The selection of SNPs was also based on their linkage disequilibrium with TPH2 rs4570625, a genetic variant with questionable functionality, which was previously associated with clinical response in our pediatric population. A total of 83 children and adolescents were clinically evaluated 12weeks after initiating antidepressant treatment with fluoxetine for the first time. Clinical improvement was assessed by reductions in depressive symptoms measured using the Children's Depression Inventory (CDI) scale. The polymorphisms rs11179002, rs60032326 and rs34517220 were, for the first time in the literature, significantly associated with higher clinical improvement. The strongest association was found for rs34517220. In particular, minor allele homozygotes showed higher score reductions on the CDI scale compared with the major allele carriers. Interestingly, this polymorphism is located in a human TPH2 TFBS for two relevant transcription factors in the serotoninergic neurons, Foxa1 and Foxa2, which together with the high level of significance found for this SNP, could indicate that rs34517220 is in fact the crucial functional genetic variant related to the fluoxetine response. These results provide new evidence for the role of regulatory genetic variants that could modulate human TPH2 expression in the SSRI antidepressant response.
与大脑血清素能系统相关的基因变异性对诸如重度抑郁症（MDD）等精神疾病的易感性以及对抗抑郁药物（如氟西汀）的反应均有重大影响。TPH2是选择性5-羟色胺再摄取抑制剂（SSRIs）药物遗传学研究中最重要的血清素能候选基因之一。本研究的目的是评估特异性位于人类TPH2转录因子结合位点（TFBSs）的调控多态性对接受氟西汀治疗的儿童和青少年临床改善的影响，这些多态性可能通过改变基因表达而发挥作用。单核苷酸多态性（SNPs）的选择还基于它们与TPH2 rs4570625的连锁不平衡，TPH2 rs4570625是一个功能存疑的基因变体，此前在我们的儿科人群中与临床反应相关。首次使用氟西汀进行抗抑郁治疗12周后，对总共83名儿童和青少年进行了临床评估。使用儿童抑郁量表（CDI）评估抑郁症状的减轻情况来评估临床改善。rs11179002、rs60032326和rs34517220多态性在文献中首次被发现与更高的临床改善显著相关。rs34517220的相关性最强。特别是，与主要等位基因携带者相比，次要等位基因纯合子在CDI量表上的得分降低幅度更大。有趣的是，这种多态性位于血清素能神经元中两个相关转录因子Foxa1和Foxa2的人类TPH2 TFBS中，再加上该单核苷酸多态性（SNP）具有高度显著性，这可能表明rs34517220实际上是与氟西汀反应相关的关键功能基因变体。这些结果为调控基因变体在SSRIs抗抑郁反应中调节人类TPH2表达的作用提供了新证据。
