基因拷贝数变异在自身免疫性甲状腺疾病发病中的作用

项目名称： 基因拷贝数变异在自身免疫性甲状腺疾病发病中的作用

项目编号： No.81471004

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 张进安

作者单位： 复旦大学

项目金额： 73万元

中文摘要： 遗传因素对自身免疫性甲状腺疾病（AITD）易感性的贡献达80%。我们及国内外前期研究发现CTLA4、Tg等基因的单核苷酸多态性（SNP）是AITD的易感因素。但是这些发现解释不了这类多基因遗传病的全部，且不同研究尚得出了不同结论。基因拷贝数变异（CNV）是近年来发现的一种新的遗传标记，通过调控基因的表达参与疾病的发生。近年来，第二代基因测序（next-generation sequencing，NGS）基因芯片等高通量技术开辟了复杂疾病遗传学研究的新纪元。NGS具有高准确度、速度快、低成本的特点。本课题拟通过目标区域捕获（基因芯片）技术在AITD核心家系中筛选易感基因的CNV，再利用NGS技术验证这些CNV区域，在更大的人群中验证AITD相关CNV区域，进而通过后续生物学功能实验验证这些CNV对基因表达的调控，以期进一步揭示AITD的遗传学发病机制。

中文关键词： 自身免疫性甲状腺疾病；拷贝数变异；Graves'病；桥本氏甲状腺炎；第二代测序

英文摘要： Genetic factors contribute up to 80% to the susceptibility of autoimmune thyroid diseases (AITD). We and others previously found the single nucleotide polymorphisms (SNP) of CTLA4, Tg, et al. are the susceptible factors. However, single gene plays little role in these polygenetic diseases. Copy number variation (CNV) is a newly found genetic marker, and it can participate in the development of disease by regulating gene expression. In recent years, the high-throughput technologies including next generation sequencing (NGS) and gene chips open a new era of the research on such complex diseases, like AITD. NGS has high accuracy, fast speed, low cost and can provide the most realible information of DNA sequence. In this project, we intend to select CNV susceptibility genes in several AITD nuclear families through target area capture (gene chips), to validate these genes related expressing CNV areas using NGS, then we will collect more samples （1000 AITD patients and 1000 normal controls）and study AITD related CNV regions in a much larger population, finally, we will verify the regulation of CNV to gene expression through the biological function experiments, which can further clarify the development mechanism of AITD, and provide a new therapy method to treat AITD.

英文关键词： autoimmune thyroid disease;copy number variation;Graves' disease;Hashimoto's thyroiditis;next generation sequencing