自噬是一个复杂的可调控生物学通路，新近研究发现自噬参与免疫调节。我们前期根据最新GWAS研究结果在大样本人群中通过遗传学多层次整合分析发现了自噬基因ATG5遗传变异通过影响自噬、凋亡、NFκB信号和I型干扰素基因参与系统性红斑狼疮（SLE）发病易感性。我们推测：自噬通路基因的遗传变异，通过反式-表达数量性状座(trans-eQTL)效应影响ATG5基因表达，并影响和ATG5交互作用的自噬相关基因、及其下游基因的表达，以基因交互作用的方式，促进SLE的发生和发展。本研究拟通过全基因组水平基于ATG5的trans-eQTL遗传学关联分析、独立人群验证、基因-基因交互作用分析、人类SLE病例-对照血清学和细胞学功能研究，以及SLE小鼠模型体内试验等功能学研究，深化多层次整合分析研究，寻找位于ATG5上游影响ATG5的表达和功能基因，以进一步明确自噬参与SLE发病的遗传学和相关分子致病机制。

Autophagy is a biologically regulated pathway, invloving in immune homeastasis adaptation.Our previous study suggested that genotypes of PRDM1-ATG5 intergenic gene polymorphisms correlated with ATG5 (cis-QTL effect) and its downstream gene expressions (trans-QTL effect), including many autophagy genes, type I IFN related genes, apoptosis related genes, and NF-κB related genes, suggesting ATG5 has a multi-facet function in lupus pathogenesis.?We thus hypothesized that genetic polymorphisms of autophagy genes may function at the upstream of ATG5 by trans-QTL effect to further modulate SLE susceptibility. We thus conduct a genetic association study at the genome-wide level, choosing eSNPs whose genotypes correlated with ATG5 gene expression.?For positive findings, we will replicate from mutiple populations or cohorts. Their functional significance will be searched by bioinformatics and the gene-gene interactions among them will also be addressed. In addition, their functions will be further checked from both human lymphocytes in vitro and from lupus mouse models in vivo. Such endeavors will broaden our views for the pathogenic roles of autophagy in SLE.