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Weighted Gene Co-expression Network Analysis Reveals Different Immunity but Shared Renal Pathology Between IgA Nephropathy and Lupus Nephritis
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...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2021
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8039522/ https://www.ncbi.nlm.nih.gov/pubmed/33854525 http://dx.doi.org/10.3389/fgene.2021.634171 |
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author | Jia, Ni-Ya Liu, Xing-Zi Zhang, Zhao Zhang, Hong |
author_facet | Jia, Ni-Ya Liu, Xing-Zi Zhang, Zhao Zhang, Hong |
author_sort | Jia, Ni-Ya |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8039522 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-80395222021-04-13 Weighted Gene Co-expression Network Analysis Reveals Different Immunity but Shared Renal Pathology Between IgA Nephropathy and Lupus Nephritis Jia, Ni-Ya Liu, Xing-Zi Zhang, Zhao Zhang, Hong Front Genet Genetics 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. Frontiers Media S.A. 2021-03-29 /pmc/articles/PMC8039522/ /pubmed/33854525 http://dx.doi.org/10.3389/fgene.2021.634171 Text en Copyright © 2021 Jia, Liu, Zhang and Zhang. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Genetics Jia, Ni-Ya Liu, Xing-Zi Zhang, Zhao Zhang, Hong Weighted Gene Co-expression Network Analysis Reveals Different Immunity but Shared Renal Pathology Between IgA Nephropathy and Lupus Nephritis |
title | Weighted Gene Co-expression Network Analysis Reveals Different Immunity but Shared Renal Pathology Between IgA Nephropathy and Lupus Nephritis |
title_full | Weighted Gene Co-expression Network Analysis Reveals Different Immunity but Shared Renal Pathology Between IgA Nephropathy and Lupus Nephritis |
title_fullStr | Weighted Gene Co-expression Network Analysis Reveals Different Immunity but Shared Renal Pathology Between IgA Nephropathy and Lupus Nephritis |
title_full_unstemmed | Weighted Gene Co-expression Network Analysis Reveals Different Immunity but Shared Renal Pathology Between IgA Nephropathy and Lupus Nephritis |
title_short | Weighted Gene Co-expression Network Analysis Reveals Different Immunity but Shared Renal Pathology Between IgA Nephropathy and Lupus Nephritis |
title_sort | weighted gene co-expression network analysis reveals different immunity but shared renal pathology between iga nephropathy and lupus nephritis |
topic | Genetics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8039522/ https://www.ncbi.nlm.nih.gov/pubmed/33854525 http://dx.doi.org/10.3389/fgene.2021.634171 |
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