SLE是典型的遗传易感性自身免疫病，GWAS研究虽发现了大量SLE风险基因及多态性变异位点(SNP),但如何识别致病性SNP并研究其功能仍是疾病基因组研究的难题。我们近期发现位于HLA-D基因调控区域的XL9序列中存在多个与抗原递呈基因异常表达相关的功能性SNP，提示该区域对自身免疫反应可能有重要调节功能。本项目拟采用靶基因测序法对中国SLE患者XL9序列进行深度序列分析，发现该序列中的功能性SNP和单倍体基因型，并揭示它们与SLE临床表型及自身抗体的相关性。深入研究XL9序列的功能性SNP是否通过影响XL9与CTCF、IRF4等转录因子的结合从而调控抗原递呈分子HLA-DRB1/DQA1的表达，分析XL9变异位点的甲基化修饰与抗原递呈基因表达调控的关系，并观察携带不同XL9等位基因型的抗原递呈细胞对T细胞分化的影响。为阐明XL9功能性变异位点在SLE发病机制中的重要作用提供实验依据。

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease with genetic predisposition. Genome-wide association studies (GWAS) have identified large amount of SLE susceptibility genes and single nucleotide polymorphism (SNP). However, how to identify the causative variants and verify their function is still a challenge. Recently we discovered many functional SNPs in XL9,one of the regulatory elements in HLA-D gene region, may modulate the aberrant expression of antigen presenting genes, suggesting that the XL9 region may have important regulatory function on autoimmunity. In this application, we are proposing to deep sequencing the XL9 region of a large cohort of Chinese SLE patients and controls using target gene sequencing technology, to identify the disease related functional variants and the haplotypes and to define their association with SLE clinical phenotypes and autoantibodies. Furthermore, we will study if the functional variants in XL9 will modulate the expression of the antigen presenting molecule HLA-DRB1/DQA1,by modifying the binding efficiency of the transcription factors such as CTCF and IRF4 with their consensus sequences in XL9. In addition, we will analyze the methylation status of the functional variants in XL9 and their regulation on the expression of antigen presenting genes, and also to observe the effect of the antigen presenting cells carrying different XL9 functional variants on the differentiation of the T lymphocytes. Our study will provide experimental evidence about the role of the functional variants in XL9 in the pathogenesis of SLE.