Jia Ni-Ya, Liu Xing-Zi, Zhang Zhao, Zhang Hong
Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China.
Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.
Front Genet. 2021 Mar 29;12:634171. doi: 10.3389/fgene.2021.634171. eCollection 2021.
Both IgA nephropathy (IgAN) and lupus nephritis (LN) are immunity-related diseases with a complex, polygenic, and pleiotropic genetic architecture. However, the mechanism by which the genetic variants impart immunity or renal dysfunction remains to be clarified. In this study, using gene expression datasets as a quantitative readout of peripheral blood mononuclear cell (PBMC)- and kidney-based molecular phenotypes, we analyzed the similarities and differences in the patterns of gene expression perturbations associated with the systematic and kidney immunity in IgAN and LN. Original gene expression datasets for PBMC, glomerulus, and tubule from IgAN and systemic lupus erythematosus (SLE) patients as well as corresponding controls were obtained from the Gene Expression Omnibus (GEO) database. The similarities and differences in the expression patterns were detected according to gene differential expression. Weighted gene co-expression network analysis (WGCNA) was used to cluster and screen the co-expressed gene modules. The disease correlations were then identified by cell-specific and functional enrichment analyses. By combining these results with the genotype data, we identified the differentially expressed genes causatively associated with the disease. There was a significant positive correlation with the kidney expression profile, but no significant correlation with PBMC. Three co-expression gene modules were screened by WGCNA and enrichment analysis. Among them, blue module was enriched for glomerulus and podocyte ( < 0.05) and positively correlated with both diseases ( < 0.05), mainly immune regulatory pathways. Pink module and purple module were enriched for tubular epithelium and correlated with both diseases ( < 0.05) through predominant cell death and extracellular vesicle pathways, respectively. In genome-wide association study (GWAS) enrichment analysis, blue module was identified as the high-risk gene module that distinguishes LN from SLE and contains and , the susceptibility genes for IgAN. In conclusion, IgAN and LN showed different systematic immunity but similarly abnormal immunity in kidney. Immunological pathways may be involved in the glomerulopathy and cell death together with the extracellular vesicle pathway, which may be involved in the tubular injury in both diseases. Blue module may cover the causal susceptibility gene for IgAN and LN.
IgA 肾病（IgAN）和狼疮性肾炎（LN）均为与免疫相关的疾病，具有复杂、多基因和多效性的遗传结构。然而，基因变异赋予免疫或导致肾功能障碍的机制仍有待阐明。在本研究中，我们使用基因表达数据集作为外周血单个核细胞（PBMC）和肾脏分子表型的定量读数，分析了与 IgAN 和 LN 中的系统性免疫和肾脏免疫相关的基因表达扰动模式的异同。来自 IgA 肾病和系统性红斑狼疮（SLE）患者以及相应对照的 PBMC、肾小球和肾小管的原始基因表达数据集从基因表达综合数据库（GEO）中获取。根据基因差异表达检测表达模式的异同。使用加权基因共表达网络分析（WGCNA）对共表达基因模块进行聚类和筛选。然后通过细胞特异性和功能富集分析确定疾病相关性。通过将这些结果与基因型数据相结合，我们确定了与疾病因果相关的差异表达基因。其与肾脏表达谱呈显著正相关，但与 PBMC 无显著相关性。通过 WGCNA 和富集分析筛选出三个共表达基因模块。其中，蓝色模块在肾小球和足细胞中富集（<0.05），与两种疾病均呈正相关（<0.05），主要为免疫调节途径。粉色模块和紫色模块分别在肾小管上皮中富集，分别通过主要的细胞死亡和细胞外囊泡途径与两种疾病相关（<0.05）。在全基因组关联研究（GWAS）富集分析中，蓝色模块被确定为区分 LN 与 SLE 的高风险基因模块，并且包含 IgAN 的易感基因 和 。总之，IgAN 和 LN 表现出不同的系统性免疫，但肾脏免疫同样异常。免疫途径可能与肾小球病变和细胞死亡以及细胞外囊泡途径共同参与，后者可能参与两种疾病的肾小管损伤。蓝色模块可能涵盖 IgAN 和 LN 的因果易感基因。
