CD58基因与系统性红斑狼疮发病机制相关性研究

Systemic lupus erythematosus (SLE) is an autoimmune disease that affects multiple organs, and genetic factors play an important role in its pathogenesis. The applicant has performed a large-scale exome-wide study for SLE, which discovered four novel SLE gene regions encompassing three novel missense variants with genome-wide significance. In addition, we found a suggestive SLE susceptibility signal in CD58 gene almost reaching genome-wide significance in the SLE exome-wide study data (P= 5.28E-08). Then the applicant found that the correlation signal was verified in the independent small samples of SLE cases - control in Chinese population (P < 0.05), but there was no statistically significant correlation in the large samples of European population. Accordingly, we speculate that the CD58 gene may be SLE specific susceptibility region in Chinese population. In order to explore the correlation between this region and SLE and reveal the potential roles in the mechanism of SLE in Chinese population, we plan to perform a further replication study for SNPs in CD58 gene in 6,000 samples. Then, we will conduct some functional experiment to reveal the important role of CD58 in onset of SLE, such as RT-PCR, eQTL and dual luciferase assay. This study is expected to find the specific susceptibility genes for Chinese which can provide theoretical basis for prediction, diagnosis and drug targets of SLE.

系统性红斑狼疮（SLE）是一种累及多脏器的自身免疫性疾病，遗传在其发病过程中起重要作用。申请人已完成大规模SLE全外显子组关联研究，发现4个新易感区域和3个编码变异。同时提示，CD58基因存在SLE潜在易感信号（P = 5.28E-08）；申请人深入研究，发现该关联信号在独立小样本汉族SLE病例-对照中被验证（P < 0.05），但在大样本欧洲人群却无统计学显著关联。据此推测，CD58基因区域可能存在汉族人特异性的SLE易感基因。为探索该区域与汉族人群SLE的关联并揭示其参与SLE的作用机制，拟采用Sequenom平台在6,000例SLE病例-对照对CD58基因变异进行分型，明确其与SLE发病风险的统计学关联；利用RT-PCR、eQTL、荧光素酶报告基因等，初步揭示SLE中该区域基因变异的作用机制。该研究预期将发现汉族人特异性易感基因，为SLE风险预测、诊疗和新药研发提供理论依据。

前期本课题组对10,103例系统性红斑狼疮（SLE）患者和16,326例对照的基因组外显子区域进行研究，在1号染色体靠近CD58基因的区域发现一个SLE提示性易感信号（P=5.28E-8），本基金拟对该候选区域易感信号进行深入研究并探索其发病机制。为对该候选易感区域开展大样本量验证，探索该区域对东亚地区其他人群SLE发病风险的影响，本课题组牵头组织韩国、日本和中国香港地区的研究团队合作开展东亚地区SLE的全基因组meta分析，对10029例SLE病例和180167例对照进行了新的全基因组基因分型，随后与各课题组既往发表的5项包含3348例SLE病例和14826例对照的SLE GWAS原始数据进行大规模的meta分析，这是迄今为止全球规模最大的SLE全基因组关联研究。我们进一步应用贝叶斯统计方法来定位SLE相关的假定因果变量，结果确定了113个遗传区域，包括46个新位点 (p<5×10−8)，其中发现CD58基因区域存在东亚地区SLE的易感基因（rs9651076, P=3.26E-13），采用DEPICT方法对SLE GWAS meta分析结果中涉及到的基因、组织和细胞进行优化，结果提出CD58是这个区域的候选致病基因（P= 8.37E−05），随后对CD58基因进行基因表达研究以及功能注释，发现CD58基因在病例中的表达高于对照，rs9651076对CD58基因的表达水平具有显著的eQTL效应，且rs9651076在一些免疫细胞中可能具有基因启动子和增强子功能，对基因表达水平可能具有调控性功能。