Integrated multiple-microarray analysis and mendelian randomization to identify novel targets involved in diabetic nephropathy
BackgroundDiabetic nephropathy (DN), which is the main cause of renal failure in end-stage renal disease, is becoming a common chronic renal disease worldwide. Mendelian randomization (MR) is a genetic tool that is widely used to minimize confounding and reverse causation when identifying the causal...
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Frontiers Media S.A.
2023-07-01
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| Series: | Frontiers in Endocrinology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fendo.2023.1191768/full |
| _version_ | 1797783979143725056 |
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| author | Chenyu Fan Yuye Gao Ying Sun |
| author_facet | Chenyu Fan Yuye Gao Ying Sun |
| author_sort | Chenyu Fan |
| collection | DOAJ |
| description | BackgroundDiabetic nephropathy (DN), which is the main cause of renal failure in end-stage renal disease, is becoming a common chronic renal disease worldwide. Mendelian randomization (MR) is a genetic tool that is widely used to minimize confounding and reverse causation when identifying the causal effects of complex traits. In this study, we conducted an integrated multiple microarray analysis and large-scale plasma proteome MR analysis to identify candidate biomarkers and evaluate the causal effects of prospective therapeutic targets in DN.MethodsFive DN gene expression datasets were selected from the Gene Expression Omnibus. The robust rank aggregation (RRA) method was used to integrate differentially expressed genes (DEGs) of glomerular samples between patients with DN and controls, followed by functional enrichment analysis. Protein quantitative trait loci were incorporated from seven different proteomic genome-wide association studies, and genetic association data on DN were obtained from FinnGen (3676 cases and 283,456 controls) for two-sample MR analysis. External validation and clinical correlation were also conducted.ResultsA total of 82 DEGs (53 upregulated and 29 downregulated) were identified through RRA integrated analysis. The enriched Gene Ontology annotations and Kyoto Encyclopedia of Genes and Genomes pathways of the DEGs were significantly enriched in neutrophil degranulation, neutrophil activation, proteoglycan binding, collagen binding, secretory granule lumen, gluconeogenesis, tricarboxylic acid cycle, and pentose phosphate pathways. MR analysis revealed that the genetically predicted levels of MHC class I polypeptide-related sequence B (MICB), granzyme A (GZMA), cathepsin S (CTSS), chloride intracellular channel protein 5, and ficolin-1 (FCN1) were causally associated with DN risk. Expression validation and clinical correlation analysis showed that MICB, GZMA, FCN1, and insulin-like growth factor 1 may participate in the development of DN, and carbonic anhydrase 2 and lipoprotein lipase may play protective roles in patients with DN.ConclusionOur integrated analysis identified novel biomarkers, including MICB and GZMA, which may help further understand the complicated mechanisms of DN and identify new target pathways for intervention. |
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| language | English |
| last_indexed | 2024-03-13T00:33:28Z |
| publishDate | 2023-07-01 |
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| series | Frontiers in Endocrinology |
| spelling | doaj.art-fce88db4b6794d7b95ed1d4622705b132023-07-10T08:50:34ZengFrontiers Media S.A.Frontiers in Endocrinology1664-23922023-07-011410.3389/fendo.2023.11917681191768Integrated multiple-microarray analysis and mendelian randomization to identify novel targets involved in diabetic nephropathyChenyu Fan0Yuye Gao1Ying Sun2Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, Beijing, ChinaKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery III, Peking University Cancer Hospital & Institute, Beijing, ChinaJiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu, ChinaBackgroundDiabetic nephropathy (DN), which is the main cause of renal failure in end-stage renal disease, is becoming a common chronic renal disease worldwide. Mendelian randomization (MR) is a genetic tool that is widely used to minimize confounding and reverse causation when identifying the causal effects of complex traits. In this study, we conducted an integrated multiple microarray analysis and large-scale plasma proteome MR analysis to identify candidate biomarkers and evaluate the causal effects of prospective therapeutic targets in DN.MethodsFive DN gene expression datasets were selected from the Gene Expression Omnibus. The robust rank aggregation (RRA) method was used to integrate differentially expressed genes (DEGs) of glomerular samples between patients with DN and controls, followed by functional enrichment analysis. Protein quantitative trait loci were incorporated from seven different proteomic genome-wide association studies, and genetic association data on DN were obtained from FinnGen (3676 cases and 283,456 controls) for two-sample MR analysis. External validation and clinical correlation were also conducted.ResultsA total of 82 DEGs (53 upregulated and 29 downregulated) were identified through RRA integrated analysis. The enriched Gene Ontology annotations and Kyoto Encyclopedia of Genes and Genomes pathways of the DEGs were significantly enriched in neutrophil degranulation, neutrophil activation, proteoglycan binding, collagen binding, secretory granule lumen, gluconeogenesis, tricarboxylic acid cycle, and pentose phosphate pathways. MR analysis revealed that the genetically predicted levels of MHC class I polypeptide-related sequence B (MICB), granzyme A (GZMA), cathepsin S (CTSS), chloride intracellular channel protein 5, and ficolin-1 (FCN1) were causally associated with DN risk. Expression validation and clinical correlation analysis showed that MICB, GZMA, FCN1, and insulin-like growth factor 1 may participate in the development of DN, and carbonic anhydrase 2 and lipoprotein lipase may play protective roles in patients with DN.ConclusionOur integrated analysis identified novel biomarkers, including MICB and GZMA, which may help further understand the complicated mechanisms of DN and identify new target pathways for intervention.https://www.frontiersin.org/articles/10.3389/fendo.2023.1191768/fulldiabetic nephropathymicroarray analysismendelian randomizationMICBGZMA |
| spellingShingle | Chenyu Fan Yuye Gao Ying Sun Integrated multiple-microarray analysis and mendelian randomization to identify novel targets involved in diabetic nephropathy Frontiers in Endocrinology diabetic nephropathy microarray analysis mendelian randomization MICB GZMA |
| title | Integrated multiple-microarray analysis and mendelian randomization to identify novel targets involved in diabetic nephropathy |
| title_full | Integrated multiple-microarray analysis and mendelian randomization to identify novel targets involved in diabetic nephropathy |
| title_fullStr | Integrated multiple-microarray analysis and mendelian randomization to identify novel targets involved in diabetic nephropathy |
| title_full_unstemmed | Integrated multiple-microarray analysis and mendelian randomization to identify novel targets involved in diabetic nephropathy |
| title_short | Integrated multiple-microarray analysis and mendelian randomization to identify novel targets involved in diabetic nephropathy |
| title_sort | integrated multiple microarray analysis and mendelian randomization to identify novel targets involved in diabetic nephropathy |
| topic | diabetic nephropathy microarray analysis mendelian randomization MICB GZMA |
| url | https://www.frontiersin.org/articles/10.3389/fendo.2023.1191768/full |
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