Graves' 病是一种常见的器官特异性自身免疫性疾病。遗传因素对Graves' 病发病影响很大，MHC区域是对其影响最大的遗传因素。由于其序列的复杂性，以前很难对大样本进行高分辨率分型，以至于目前并不清楚此区域内确切的疾病相关变异。厘清HLA基因变异对Graves' 病遗传易感性的影响对解读其遗传机制至关重要。我们将用新一代测序技术对经典HLA基因在病例对照样本中进行测序，确定HLA基因影响疾病易感性的关键变异；进而对大家系样本进行测序，鉴定在特定家系中起作用的变异；对比群体与家系样本的结果，分析常见变异与罕见变异对疾病的不同贡献；结合课题组前期的研究结果，对HLA区域疾病变异与其它疾病变异进行统计学相互作用分析，并对疾病相关变异之间的累积作用进行分析；然后，通过分子生物学手段研究HLA分子与甲状腺特异性蛋白之间的相互作用机制；最后，以Graves' 病为模型探讨复杂疾病的遗传结构。

Graves' disease (GD) is a common organ-specific autoimmune disease. Genetic factors have a great influence on the development of Graves' disease. There are sound data coming from previous studies demonstrating that the MHC region was the greatest genetic factor for Graves' disease susceptibility. It is difficult to genotype the HLA genes in a larger sample with high resolution for the complexity within the HLA region sequence. Therefore, the causative disease associated variants in the HLA gene region were still unknown. To make the causative disease associated variants clear is of vital importance for understanding the genetics structure of Graves' disease. In the future study, we will firstly sequence the classical HLA genes in a big case-control sample using the next generation sequencing technology to identify the causative variants. Then, we will sequence a sample consisting of big Graves' disease pedigrees to identify the causative variants in certain pedigrees. Next, we will compare the results from the case-control study and the pedigree study to analyze the respective contribution of common and rare disease variation to disease risk. Combining the results from our previous study, we will analyze the statistical interaction between the disease variation of the HLA genes and other genes, and/or the additive influence of the disease-associated variants to disease risk. After that, we will dissect the molecular interaction by the binding energetics between the HLA molecular and the peptides consisting of the antigen of thyroid specific protein employing molecular biology techniques. Finally, we will try to investigate the genetic structure of complex disease using Graves' disease as a model.