色氨酸羟化酶2基因（TPH2）和环境相互作用与抗抑郁剂疗效的关系：表观遗传学机制研究

Depression is a major cause of disability world-wide, yet a large proportion of patients respond inadequately to current antidepressant treatment. Two factors that contribute to the differences between individuals in their response to antidepressant drugs are genetic variability and history of stressful life events. We have identified some of the genetic factors that contribute to this individual variability and also shown that a few of these genes, particularly those in the serotonin neurotransmitter system important in antidepressant action, interact with life stressors to influence response to treatment. One of these genes is that for tryptophan hydroxylase2 (TPH2), which is responsible for synthesis of serotonin in the brain. We have identified several polymorphisms in this gene associated with response to treatment that also show interactions with early life stress. The mechanisms whereby early life stress can influence treatment response are unclear, but may include epigenetics, whereby environmental factors may modify the genome. One epigenetic mechanism, DNA methylation, can influence gene expression, as can genetic polymorphisms. We aim to test the involvement of DNA methylation of the TPH2 gene in the clinical response to antidepressant treatment and its relationship to early life stress, and to investigate the involvement of another gene, MTHFR, which influences DNA methylation levels as well as being a risk factor for depression. We shall also use an animal model of depression to test the influence of maternal separation stress, and chronic treatment with antidepressant drugs, on TPH2 DNA methylation. Our findings should indicate the role of DNA methylation in understanding the relationships between environmental factors, genetic variability and treatment response in patients with depression.

本研究将基于抑郁症"表观遗传学说"、抗抑郁药物遗传学研究进展以及本研究组前期研究成果，从模式动物和临床研究两个层面探讨色氨酸羟化酶2（TPH2）基因表观遗传修饰与抗抑郁剂疗效相关性。首先，利用母婴分离大鼠模型，探讨SSRI和早期创伤经历对大鼠海马区及前额叶区TPH2基因启动子区DNA甲基化的影响，以及与TPH2基因和蛋白表达的相关性；其次基于我们现有的抗抑郁剂治疗抑郁症患者临床数据库和DNA样本库，探讨TPH2基因启动子区DNA甲基化水平与抗抑郁剂疗效的相关性，同时分析甲基代谢限速酶亚甲基四氢叶酸还原酶（MTHFR）基因多态性和TPH2基因DNA甲基化相互作用对抗抑郁剂疗效的影响。最后，综合分析THP2的表观遗传调控及其与基因、环境的相互影响在抗抑郁剂药效中重要作用，为抑郁症的有效治疗提供新的实验依据，也为探讨情感障碍分子机制提供新的思路和证据。

本研究基于抑郁症“表观遗传学说”、抗抑郁药物遗传学研究进展以及本研究组前期研究成果，探讨色氨酸羟化酶2（TPH2）基因甲基化水平与抑郁症疾病/抗抑郁剂疗效的相关性。通过建立完善的抗抑郁剂治疗抑郁症患者和对照组的临床数据库和DNA样本库，探讨TPH2基因的DNA甲基化水平与抑郁症疾病发生的相关性，以及TPH2基因的DNA甲基化水平抗抑郁剂疗效的相关性，同时分析甲基代谢限速酶亚甲基四氢叶酸还原酶（MTHFR）基因多态性和TPH2基因DNA甲基化相互作用对抑郁症发生/抗抑郁剂疗效的影响。综合分析THP2的表观遗传调控及其与基因、环境的相互影响在抑郁症发生和抗抑郁剂药效中重要作用，为抑郁症的诊断和有效治疗提供新的实验依据，也为探讨情感障碍分子机制提供新的思路和证据。.目前得到了以下结果：1) TPH2基因的部分CpG位点甲基化程度在抑郁症和对照组间存在显著性差异；在抑郁症组和对照组，MTHFR SNPs的不同基因型分组中TPH2的CpG位点甲基化水平有显著差异；CTQ-SF和NLES在抑郁症组和对照组间存在显著性差异；2) TPH2基因的部分CpG位点甲基化程度在痊愈症和未愈组间存在显著性差异；痊愈组和未愈组的MTHFR基因SNPs rs1801133，rs2274976基因型分布存在显著性差异；在痊愈症和未愈组， MTHFR SNPs的不同基因型分组中TPH2的CpG位点甲基化水平有显著差异；TPH2 CpG位点TPH2_1_77，TPH2_1_163，TPH2_9_160与早期应激（CTQ-SF）相互作用影响抗抑郁药物疗效。.结论：抑郁症的疾病发生和抗抑郁剂疗效可能与TPH2的CpG位点甲基化程度有关，MTHFR的基因多态性影响了抗抑郁药物的疗效，MTHFR基因SNPs的不同基因型间甲基化程度不同可能与抑郁症疾病发生有关，与抗抑郁剂疗效相关，早期和近期生活事件与抑郁症的发生有关，早期生活事件和TPH2 CpG位点甲基化水平的相互作用会影响到抗抑郁剂疗效。

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