新的易感基因C1QTNF6在Graves病中的作用及其机制研究

Graves'disease（GD） is an organ-specific autoimmune diseases triggered by combination of genetic susceptibility, environmental encounters and hormonal factors. It is reported that T lymphocyte subsets Th1/Th2 imbalance play an important role in GD pathogenesis. Our previous genome-wide association study （GWAS） identified a novel GD susceptibility gene C1QTNF6, with rs229527 as the susceptibility SNP, and its genotypes were correlated with the mRNA expression of C1QTNF6 and IL-10 in CD4+T lymphocyte；Previous GWAS also showed that C1QTNF6 gene was associated with type 1 diabetes mellitus （T1DM）and vitiligo, and the gene encoded protein CTRP6 increased the expression of IL-10 in macrophages. It is known that IL-10 is a Th2 type cytokine. Therefore, we speculate that the newly identified GD susceptibility genes C1QTNF6 and SNP may have an important effect on GD predisposition by regulating the differentiation of lymphocyte. We intend to conduct a thorough research based on this hypothesis.

弥漫性甲状腺肿伴甲亢（Graves’disease，GD）, 是一种由多个遗传因素、环境因素以及激素相互作用的器官特异性自身免疫性疾病，研究发现T淋巴细胞亚群Th1/Th2失衡是GD发病重要机制。我们前期全基因组关联分析（GWAS）研究识别了一个新的GD易感基因C1QTNF6，其易感SNP是rs229527，并且该SNP不同等位基因型在CD4+T淋巴细胞中与C1QTNF6基因和细胞因子IL-10的表达存在相关性；既往GWAS研究也发现C1QTNF6基因是自身免疫疾病1型糖尿病（T1DM）和白癜风（Vitiligo）的易感基因，且该基因编码蛋白CTRP6可以诱导单核巨噬细胞IL-10表达增加。已知IL-10是一种Th2类型细胞因子，因此，我们推测新识别的GD易感基因和易感SNP可能通过影响免疫细胞亚群的分化，来发挥其对免疫功能的调节，从而参与甲亢的发生。本项目将围绕我们这一假设进行深入研究。

在本项目资助下，课题组发现组蛋白去甲基化酶Jumonji domain-containing-3 (JMJD3)在甲状腺乳头状癌（PTC）中高表达，且阻断JMJD3可以下调PTC细胞的增殖和迁移，而 JMJD3通过E2/ ERα在PTC细胞中高表达；进一步研究表明高表达的JMJD3可以激活NF-κB信号通路，通过NF-κB信号通路促进PTC细胞的增殖和迁移，导致甲状腺乳头状癌的发生和发展。课题组还研究了组蛋白甲基化转移酶EZH2在甲状腺乳头状癌（PTC）中的作用，研究发现EZH2在PTC细胞系和PTC组织中高表达，下调EZH2的表达会抑制PTC细胞的增殖和迁移，而雌激素(E2)可以通过ERα上调EZH2在PTC中的表达，表明EZH2在肿瘤细胞的增殖和迁移作用可能是通过E2/ ERα。上述研究结果表明JMD3和EZH2在PTC的增殖和转移中具有重要作用，为开发针对JMJD3和EZH2 靶点的特异性抑制剂治疗PTC提供了科学依据。