自身免疫性甲状腺疾病遗传变异在介导AKT/mTOR信号通路及其与碘营养互作对甲状腺细胞生物学功能的研究

Autoimmune thyroid diseases (AITD) can mainly involve complex interactions between genetic susceptibility and environmental exposure. A recent study has demonstrated that excess iodine promotes apoptosis of thyroid follicular epithelial cells via AKT/mTOR pathway. However, there had been no research performed to determine whether the important environmental factor iodine could interact with AITD susceptibility genes. In our previous studies, we found iodine concentration was closely connected with thyroid disease and the aberrant DNA methylation in the promoter regions of AITD susceptibility genes. Hence, we put forward a hypothesis that candidate genes promote the progression of AITD through AKT/mTOR pathway and iodine concentration could affect epigenetic change which causes the susceptible individuals to AITD. In our research, we are going to verify the associated relationship between genetic variants and AITD on the basic of our previous target region sequencing. At the same time, the genetic mutants will be constructed and transfected to thyroid cell and the role of genetic variation play in thyroid cell will be tested by cytology and molecular biology techniques. Our further experiments will be performed to elucidate the underlying mechanism between AITD susceptibility genes and AKT/mTOR pathway. And then, we will handle the relations among iodine concentration, epigenetic and genetic variants. Finally, we will design a prospective study to assess the relationship between iodine nutrition and those susceptible individuals to AITD. Taken together, our study will provide experimental basis for the possible pathogenesis and early diagnosis of AITD. We will make efforts for providing moderate amount of iodine for individuals and early-stage prevention and treatment of high-risk populations.

自身免疫性甲状腺疾病(AITD)是环境-遗传互作的复杂疾病。高碘通过AKT/mTOR信号通路诱导甲状腺细胞的凋亡，但碘与AITD易感基因互作的机制尚不清楚。本课题组前期发现，碘过量与甲状腺疾病相关，并且AITD易感基因可能发生了甲基化水平的改变。故提出假说：易感基因通过介导AKT/mTOR信号通路促进AITD的发生，并在碘的影响下，发生了表观遗传学的改变使携带易感基因的个体发病。本项目拟在前期高通量测序基础上，扩大样本量验证遗传变异与AITD的相关性，同时构建突变体、转染甲状腺细胞，通过细胞及分子学技术验证遗传变异在甲状腺细胞中发挥的功能，初步探讨AKT/mTOR信号通路在其中发挥的作用，并分析碘-表观遗传-基因变异与AITD的关系，最后前瞻性评估碘与AITD易感基因携带者发病及转归的关系。本研究将为AITD的发病机制及早期诊断提供实验依据，为人群科学补碘、高危人群的早期防治做出努力。

自身免疫性甲状腺疾病(AITD)是环境-遗传互作的复杂疾病，包括Graves病(GD)和桥本甲状腺炎(HT)。研究发现本地区 40~60岁女性群体亚临床甲状腺功能减退症、HT及甲状腺结节患病率高于当地总人群水平，且不同月经状态女性单纯 TPOAb 阳性率不同。152个基因目标区域高通量测序发现，54个基因的6527个SNP位点与AITD发生有关。GD病例组中有TPO、ARID5B等11个基因的65个SNP位点回归分析有意义；HT组有BACH2、RNASET2、TG、TPO等15个基因的57个SNP位点回归分析有意义，其中，BACH2多态性与HT疾病关联最强。同时通过蛋白预测等软件分析，初步确认了TG、SLC26A4，IFIH1等15个基因的33个罕见致病突变位点。TPO 基因 rs4927631及2071403 位点与本地区人群的HT发病有关联。CTLA4基因rs231775位点多态性与本地区AITD 显著相关，且该位点的 GG 基因型 TgAb 水平较其他基因型更高。

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