基于免疫易感基因多效性挖掘系统性红斑狼疮全新易感基因及其功能研究

系统性红斑狼疮（SLE）是一种具有遗传特征的自身免疫复杂疾病。申请人前期参与了已知60个SLE易感易感基因中超过20个基因的证实，发现部分SLE易感基因具有多效性，同时是其他自身免疫疾病的易感基因。然而前期SLE易感基因挖掘并未充分利用此疾病遗传共性。本研究拟利用迄今为止最大的跨人群SLE全基因组分型数据（GWAS），基于已知其他自身免疫疾病易感基因，寻找全新SLE易感基因；这在国内外尚属首次。我们初步挖掘到包括CD226等四个潜在易感基因，拟通过后续独立样本人群验证其SLE易感性，并后续探讨其SLE相关功能机制。其中CD226携带的功能性遗传变异的SLE易感性已被先期验证，拟通过分子生物学技术建立其已证功能遗传变异到蛋白功能之间的关联。本项目的实施为进一步揭示SLE发病机制，寻找不同免疫疾病特异的治疗标记提供线索；从而为SLE的个性化医疗奠定坚实的遗传理论和实验基础。

Systemic lupus erythematous (SLE) is an autoimmune disease characterized by strong genetic component. More than 60 SLE susceptibility genes were identified so far. Pervasive pleiotropy was detected among SLE susceptibility genes and other immunological diseases. However, this piece of information was not fully addressed for searching new SLE susceptibility genes in couple with sample size, and lack of functional validation for susceptibility gene with SLE. In this study, making use of existing GWAS datasets on three trans-ethnic populations in Chinese and European respectively, we propose to look for new SLE susceptibility genes in the pool of the established susceptibility genes from three typical autoimmune diseases including Type I diabetes, Rheumatoid Arthritis and Inflammatory Bowel diseases. Preliminary results showed four prominent candidate susceptibility genes, which are await for further validation using more independent cohorts. We replicated the one of the four candidatures for susceptibility with SLE in CD226. We will further clarify the underlying mechanisms for the CD226 and other potential susceptibility genes for SLE.