单相抑郁症与5-HTR信号转导通路基因-环境作用机制研究

Depression has caused widespread concern because of the high incidence and high recurrence rate, the WHO expected that in 2020, the depression will become the second dangerous killer of the human, and its pathogenesis is still not clear. 5-HT system dysfunction is the main hypothesis of genetic predisposition to depression. But there was rarely research involved 5-HT receptor signal transduction pathway candidate gene such as 5-HT1A receptor gene, 5-HT2A receptor gene, G-protein GNβ3 gene and CREB gene polymorphism. And the relationship between the depression and gene-enviroment interaction has not yet comfirmed currently. In the study, with the principle of informed consent, the case-control study is commited, and 600 unipolar depression patients of the First Affiliated Hospital of Harbin Medical University and 600 healthy persons were invited in this study. We collected the peripheral blood samples to investigate the related risk factors of depression. Single base extension SNP genotyping technology(SNaPshot) is commited to detect the genetic polymorphism. At the same time, the drop through a multipel-factor-dimensional method and logistic regression analysis is performed to analyze the relationship of gene-gene and gene-enviroment interaction, and explore the affection of genetic susceptibility and enviroment factors for unipolar depression. Ultimately we hope to clarify the pathogenesis of unipolar depression, and prpvide the basis for the prevention and early diagnosis and treatment of depression by the study.

抑郁症(Depression)以高发病率、高复发率引起广泛关注，WHO预计2020年抑郁症将成为人类的第二大杀手，而其发病机制至今尚未清楚。5-HT系统功能紊乱是抑郁症遗传易感性的主要假说，但目前涉及5-HT受体及其信号转导通路相关候选基因5-HT1A、5-HT2A、5-HT1B受体与G蛋白的GNβ3、CREB的基因多态性及基因-环境交互作用与抑郁症的关系尚未见到。本研究在知情同意的原则下，采用病例对照的研究方法，在哈尔滨医科大学附属第一医院收集单相抑郁症患者和对照者各600 例，采集外周静脉血并调查相关危险因素；单碱基延伸SNP分型技术（SNaPshot）方法检测基因多态性；通过多因子降维法、logistic 回归等方法分析基因-基因、基因-环境之间交互作用与单相抑郁症的关系，探索遗传易感因素和环境因素对单相抑郁症的影响，阐明单相抑郁症的发病机制，为抑郁症的预防及早期诊治提供依

抑郁症已经成为影响人类健康的全球性社会与经济问题。在抑郁症发病机制的研究中，五羟色胺（5-HT）系统功能紊乱假说受到广泛关注。5-HT信息传递需要经过突触前神经元递质释放以及与突触后神经元受体结合实现信号的识别、转移与转换等过程，即细胞信号转导。5-HT信号转导通路相关基因存在着多种单核甘酸多态性变异，这种变异使个体处于抑郁症的高风险状态，并且在一定环境因素的刺激下即可能发病。因此，本研究以中国北方地区600名汉族单相抑郁患者和600名汉族健康对照为研究对象，选取5-HT信号转导通路上五个基因的十五个单核甘酸多态性位点作为遗传因素，探讨5-HT信号转导通路基因及其交互作用与抑郁症的关系；以负性生活事件和童年期创伤性事件作为环境因素，进一步探究5-HT信号转导通路基因-环境交互作用与抑郁症的关联，以阐明抑郁症的发病机制。结果发现5-HT1AR rs6295、rs878567、rs10042486，5-HT2AR rs6311、rs6313，GNβ3 rs5443位点多态性与抑郁症存在明显关联。5-HT1AR单倍体型rs6295T-rs1364043T-rs878567G-rs10042486C、5-HT2AR单倍体型 rs7997012G- rs6311C-rs6313C和rs7997012G-rs6311T-rs6313T与抑郁症有明显关联； 5-HT1AR rs6295，5-HT2AR rs6311、rs6313，GNβ3 rs5443与负性生活事件之间存在交互作用；5-HT1AR rs6295、rs878567、rs10042486，CREB1 rs6740584、rs2551941、rs2253206与童年创伤之间的交互作用增加个体罹患抑郁症的风险。本研究结果不仅为抑郁症易感性的个体化预防及临床治疗提供依据，而且为研发具有新靶点的抗抑郁药及有效的心理治疗等多个途径解决抑郁症难题提供指导作用，以取得更好的治疗效果。