Abstract
BackgroundImmunoglobulin A nephropathy (IgAN) is the leading cause of end-stage kidney disease. Previous mRNA microarray profiling studies of IgAN revealed inconsistent data. We sought to identify the aberrantly expressed genes and biological pathways by integrating IgAN gene expression datasets in blood cells and performing systematically experimental validation. We also explored the relationship between target genes and galactose-deficient IgA1 (Gd-IgA1) in IgAN.MethodsWe retrieved Gene Expression Omnibus (GEO) datasets of IgAN. Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were used for functional analysis. Deep sequencing on RNA isolated from B cells was used for microarray validation. The relationship between target mRNA expressions and Gd-IgA1 levels in serum were also studied.ResultsThree studies with microarray expression profiling datasets met our inclusion criteria. We identified 655 dyregulated genes, including 319 up-regulated and 336 down-regulated genes in three GEO datasets with a total of 35 patients of IgAN and 19 healthy controls. Based on biological process in GO term, these dyregulated genes are mainly related to pentose-phosphate shunt, non-oxidative branch, post-embryonic camera-type eye development and leukocyte activation. KEGG pathway analysis of microarray data revealed that these aberrantly expressed genes were enriched in human T-cell leukemia virus 1 infection, proteoglycans in cancer, intestinal immune network for IgA production and autophagy. We further performed deep sequencing on mRNAs isolated from B cells of an independent set of five patients with IgAN and three healthy persons with the same clinical and demographic characteristics. Seventy-seven genes overlapped with 655 differentially regulated genes mentioned above, including 43 up-regulated and thirty-four down-regulated genes. We next investigated whether these genes expression correlated with Gd-IgA1 levels in IgAN patients. Pearson correlation analyses showed PTEN (phosphatase and tensin homolog) was the most powerful gene negatively correlated with Gd-IgA1 levels.ConclusionsThese results demonstrated that dyregulated genes in patients with IgAN were enriched in intestinal immune network for IgA production and autophagy process, and PTEN in B cells might be involved in the mechanism of Gd-IgA1 production.
Highlights
Immunoglobulin A nephropathy (IgAN) is the leading cause of end-stage kidney disease
The initial event in the pathogenesis of IgAN is the production of galactosedeficient IgA1 (Gd-IgA1) [3], which lead to IgA1 selfaggregation, IgA1–IgG immune complex formation, and sequential deposition in the kidney [4, 5]
Differential gene expressions in IgAN patients A total of 655 genes were identified differentially expressed in patients of IgAN group compared with controls across three microarray datasets (P < 0.05)
Summary
Immunoglobulin A nephropathy (IgAN) is the leading cause of end-stage kidney disease. Previous mRNA microarray profiling studies of IgAN revealed inconsistent data. Comprehensive gene set enrichment analysis could help us overcome these limitations and control such confounding factors by increasing statistical power, leading to more robust, reproducible and accurate predictions for identifying differently expressed genes [9, 10]. Such studies have been successfully used to identify gene signatures in many diseases [11,12,13]
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