Abstract
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 (P < 0.05) and positively correlated with both diseases (P < 0.05), mainly via immune regulatory pathways. Pink module and purple module were enriched for tubular epithelium and correlated with both diseases (P < 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 PSMB8 and PSMB9, 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.
Highlights
Chronic glomerulonephritis is a common cause of endstage renal disease (ESRD), and most patients require renal replacement therapy to survive
Comparison of Differential gene expression (DGE) log2 fold change signatures revealed a significant overlap in renal expression profiles
There is no report about the correlation between IgA nephropathy (IgAN) and lupus nephritis (LN) expression profiles, and our study first demonstrated that IgAN and LN have independent systematic immunity, but share common susceptibility genes in kidney, and identified the shared causal gene may act dominantly via immunological pathways to trigger glomerular injury, while the death and extracellular vesicle pathways were implicated as the common mechanism underlying the development of renal tubular lesions
Summary
Chronic glomerulonephritis is a common cause of endstage renal disease (ESRD), and most patients require renal replacement therapy to survive. IgA nephropathy (IgAN) and lupus nephritis (LN) is the most common primary and secondary glomerular diseases, respectively, and tend to affect young adults, with nearly 20% of patients progressing to ESRD after 10 years because of limited drug treatment options (Mahajan et al, 2020; Natale et al, 2020) Both diseases have complex and varied clinical manifestations, many overlaps have been noted. Genetic variants that interact with environmental and epigenetic risks regulate gene expression in intermediate phenotypes of peripheral blood mononuclear cell (PBMC) and kidney, which lead to clinical symptoms such as proteinuria, hematuria, renal insufficiency, and pathological changes in the kidney. These symptoms are manifested as different clinical syndromes, such as IgAN and LN. In this study, we explored the systematic and regional immunity in IgAN and LN patients through weighted gene co-expression network analysis (WGCNA) of PBMC and kidney expression profiles available in public databases to improve understanding of the pathogenesis and develop targeted therapies
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