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Identification of novel therapeutic targets for chronic kidney disease and kidney function by integrating multi-omics proteome with transcriptome

التفاصيل البيبلوغرافية
العنوان: Identification of novel therapeutic targets for chronic kidney disease and kidney function by integrating multi-omics proteome with transcriptome
المؤلفون: Shucheng Si, Hongyan Liu, Lu Xu, Siyan Zhan
المصدر: Genome Medicine, Vol 16, Iss 1, Pp 1-20 (2024)
بيانات النشر: BMC, 2024.
سنة النشر: 2024
المجموعة: LCC:Medicine
LCC:Genetics
مصطلحات موضوعية: Chronic kidney disease, Kidney function, Mendelian randomization, Proteome, Transcriptome, Therapeutic targets, Medicine, Genetics, QH426-470
الوصف: Abstract Background Chronic kidney disease (CKD) is a progressive disease for which there is no effective cure. We aimed to identify potential drug targets for CKD and kidney function by integrating plasma proteome and transcriptome. Methods We designed a comprehensive analysis pipeline involving two-sample Mendelian randomization (MR) (for proteins), summary-based MR (SMR) (for mRNA), and colocalization (for coding genes) to identify potential multi-omics biomarkers for CKD and combined the protein–protein interaction, Gene Ontology (GO), and single-cell annotation to explore the potential biological roles. The outcomes included CKD, extensive kidney function phenotypes, and different CKD clinical types (IgA nephropathy, chronic glomerulonephritis, chronic tubulointerstitial nephritis, membranous nephropathy, nephrotic syndrome, and diabetic nephropathy). Results Leveraging pQTLs of 3032 proteins from 3 large-scale GWASs and corresponding blood- and tissue-specific eQTLs, we identified 32 proteins associated with CKD, which were validated across diverse CKD datasets, kidney function indicators, and clinical types. Notably, 12 proteins with prior MR support, including fibroblast growth factor 5 (FGF5), isopentenyl-diphosphate delta-isomerase 2 (IDI2), inhibin beta C chain (INHBC), butyrophilin subfamily 3 member A2 (BTN3A2), BTN3A3, uromodulin (UMOD), complement component 4A (C4a), C4b, centrosomal protein of 170 kDa (CEP170), serologically defined colon cancer antigen 8 (SDCCAG8), MHC class I polypeptide-related sequence B (MICB), and liver-expressed antimicrobial peptide 2 (LEAP2), were confirmed. To our knowledge, 20 novel causal proteins have not been previously reported. Five novel proteins, namely, GCKR (OR 1.17, 95% CI 1.10–1.24), IGFBP-5 (OR 0.43, 95% CI 0.29–0.62), sRAGE (OR 1.14, 95% CI 1.07–1.22), GNPTG (OR 0.90, 95% CI 0.86–0.95), and YOD1 (OR 1.39, 95% CI 1.18–1.64,) passed the MR, SMR, and colocalization analysis. The other 15 proteins were also candidate targets (GATM, AIF1L, DQA2, PFKFB2, NFATC1, activin AC, Apo A-IV, MFAP4, DJC10, C2CD2L, TCEA2, HLA-E, PLD3, AIF1, and GMPR1). These proteins interact with each other, and their coding genes were mainly enrichment in immunity-related pathways or presented specificity across tissues, kidney-related tissue cells, and kidney single cells. Conclusions Our integrated analysis of plasma proteome and transcriptome data identifies 32 potential therapeutic targets for CKD, kidney function, and specific CKD clinical types, offering potential targets for the development of novel immunotherapies, combination therapies, or targeted interventions.
نوع الوثيقة: article
وصف الملف: electronic resource
اللغة: English
تدمد: 1756-994X
Relation: https://doaj.org/toc/1756-994X
DOI: 10.1186/s13073-024-01356-x
URL الوصول: https://doaj.org/article/d9c6148dbb7b4845967a5c2162e4df9d
رقم الأكسشن: edsdoj.9c6148dbb7b4845967a5c2162e4df9d
قاعدة البيانات: Directory of Open Access Journals
الوصف
تدمد:1756994X
DOI:10.1186/s13073-024-01356-x