Weighted Gene Co-expression Network Analysis Reveals Different Immunity but Shared Renal Pathology Between IgA Nephropathy and Lupus Nephritis

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.

Identification and validation of glomerulotubular crosstalk genes mediating IgA nephropathy by integrated bioinformatics

“…Not only that, co-occurrences of IgAN and LN were found in some patients [ 36 ]. The results of our study are basically consistent with the previous studies [ 16 , 37 ].…”

Identification of toll‐like receptor 5 and acyl‐CoA synthetase long chain family member 1 as hub genes are correlated with the severe forms of COVID‐19 by Weighted gene co‐expression network analysis

“…We exacted the clinical severity from the original set as the input data for WGCNA analysis. A soft‐threshold power of 18 was used for the analysis to achieve approximate scale‐free topology ( R 2 > 0.8) [ 17 ]. Next, the topological overlap matrix (TOM) and dissimilarity TOM were created by TOM similarity and dissimilarity modules.…”

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“…Patients will develop symptoms such as edema proteinuria and hypertension [3]. At present, the speci c pathogenesis is not clear, and there is no effective targeted therapy [4]. If the treatment is not timely, end-stage renal disease (ESRD) will be developed [5][6].…”