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已发表论文
TIMP4 作为膜性肾病潜在的补充生物标志物和治疗靶点：一项多组学研究及临床验证
Authors Chen Q, Wang G, Zhao R, Hu Q, Li J, Wang Y, Ran J, Huang Q, Yu G, Luo Y, Liao X
Received 7 June 2025
Accepted for publication 15 October 2025
Published 25 October 2025 Volume 2025:18 Pages 14755—14769
DOI https://doi.org/10.2147/JIR.S545422
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 2
Editor who approved publication: Dr Wenjian Li
Qingsong Chen, Gang Wang, Ruo Zhao, Qiyuan Hu, Jiayun Li, Yuting Wang, Jingyang Ran, Qi Huang, Guiquan Yu, Yanjia Luo, Xiaohui Liao
Department of Nephrology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China
Correspondence: Yanjia Luo, Email 300926@hospital.cqmu.edu.cn Xiaohui Liao, Email lxh@hospital.cqmu.edu.cn
Background: Despite genome-wide association studies having revealed risk loci for membranous nephropathy (MN), the functional mechanisms linking genetic variants to disease pathogenesis remain poorly understood.
Methods: We implemented a multi-stage analytical framework, integrating proteome-wide association studies (PWAS) and transcriptome-wide association studies (TWAS) to systematically prioritize MN-associated biomarkers. Genetic causality was rigorously established through summary data-based Mendelian randomization (SMR) and Bayesian colocalization analysis. Clinical validation was performed in a MN cohort. Additionally, single-cell transcriptomic profiling resolved cell-type-specific expression patterns of candidate targets. The therapeutic potential was further evaluated through drug target interaction and molecular docking.
Results: PWAS identified three proteins associated with MN (PLA2R1, LY75, TIMP4), while TWAS of whole blood and kidney cortex tissues implicated significant associations for LY75, POLR2I, and NFKB1 in MN. TIMP4 was uniquely prioritized as a high-confidence candidate through concordant evidence from PWAS significance (P = 2.67 × 10− 2), causal association by SMR (PSMR = 3.61 × 10− 4, PHEIDI = 3.49 × 10− 1), and genetic colocalization (PP.H4 = 8.01 × 10− 1). Clinically, serum TIMP4 levels were significantly elevated in MN patients versus controls (2267.1 vs 1581.4 pg/mL, P < 0.001). Single-cell analysis revealed TIMP4 expression was predominant in endothelial cells, mesangial cells, fibroblasts and proximal tubule cells. Molecular docking showed the binding between TIMP4 and potential therapeutic drugs.
Conclusion: This study suggests TIMP4 may serve as a novel complementary biomarker and potential therapeutic target in MN. Systematic integration of multi-omics and clinical data provides promising insights for future drug development and mechanistic exploration.
Keywords: membranous nephropathy, multi-omics, proteome-wide association study, transcriptome-wide association study, genome-wide association study
Department of Nephrology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China
Correspondence: Yanjia Luo, Email 300926@hospital.cqmu.edu.cn Xiaohui Liao, Email lxh@hospital.cqmu.edu.cn
Background: Despite genome-wide association studies having revealed risk loci for membranous nephropathy (MN), the functional mechanisms linking genetic variants to disease pathogenesis remain poorly understood.
Methods: We implemented a multi-stage analytical framework, integrating proteome-wide association studies (PWAS) and transcriptome-wide association studies (TWAS) to systematically prioritize MN-associated biomarkers. Genetic causality was rigorously established through summary data-based Mendelian randomization (SMR) and Bayesian colocalization analysis. Clinical validation was performed in a MN cohort. Additionally, single-cell transcriptomic profiling resolved cell-type-specific expression patterns of candidate targets. The therapeutic potential was further evaluated through drug target interaction and molecular docking.
Results: PWAS identified three proteins associated with MN (PLA2R1, LY75, TIMP4), while TWAS of whole blood and kidney cortex tissues implicated significant associations for LY75, POLR2I, and NFKB1 in MN. TIMP4 was uniquely prioritized as a high-confidence candidate through concordant evidence from PWAS significance (P = 2.67 × 10− 2), causal association by SMR (PSMR = 3.61 × 10− 4, PHEIDI = 3.49 × 10− 1), and genetic colocalization (PP.H4 = 8.01 × 10− 1). Clinically, serum TIMP4 levels were significantly elevated in MN patients versus controls (2267.1 vs 1581.4 pg/mL, P < 0.001). Single-cell analysis revealed TIMP4 expression was predominant in endothelial cells, mesangial cells, fibroblasts and proximal tubule cells. Molecular docking showed the binding between TIMP4 and potential therapeutic drugs.
Conclusion: This study suggests TIMP4 may serve as a novel complementary biomarker and potential therapeutic target in MN. Systematic integration of multi-omics and clinical data provides promising insights for future drug development and mechanistic exploration.
Keywords: membranous nephropathy, multi-omics, proteome-wide association study, transcriptome-wide association study, genome-wide association study