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Updated: Jun 11, 2025
Comparative Proteomic Analysis of Whole Kidney, Medulla, and Cortical Tubules in Diabetic Pathogenesis of Kidney Injury in Mice
Published on: May 2, 2025
Proteome-wide mendelian randomization identifies novel therapeutic targets for chronic kidney disease
Pin Zhao1, Zhenhao Li1, Shilong Xue1
1Department of Urology, The First Affiliated Hospital of Zhengzhou University, No.1 East Jianshe Road, District of Erqi, Zhengzhou, 450052, Henan, People's Republic of China.
Abstract:
There is an urgent need to pinpoint novel targets for drug discovery in the context of chronic kidney disease (CKD), and the proteome represents a significant pool of potential therapeutic targets. To address this, we performed proteome-wide analyses using Mendelian randomization (MR) and colocalization techniques to uncover potential targets for CKD. We extracted summary-level data from the ARIC study, focusing on 7213 European American (EA) individuals and 4657 plasma proteins. To broaden our analysis, we incorporated genetic association data from Icelandic cohorts, thereby enhancing our investigation into the correlations with chronic kidney disease (CKD), creatinine-based estimated glomerular filtration rate (eGFRcrea), and estimated glomerular filtration rate (eGFR). We utilized genetic association data from the GWAS Catalog, including CKD (765,348, 625,219 European ancestry and 140,129 non-European ancestry), eGFRcrea (1,004,040, European ancestry), and eGFR (567,460, European ancestry). Employing MR analysis, we estimated the associations between proteins and CKD risk. Additionally, we conducted colocalization analysis to evaluate the existence of shared causal variants between the identified proteins and CKD. We detected notable correlations between levels predicted based on genetics of three circulating proteins and CKD, eGFRcrea, and eGFR. Notably, our colocalization analysis provided robust evidence supporting these associations. Specifically, genetically predicted levels of Transcription elongation factor A protein 2 (TCEA2) and Neuregulin-4 (NRG4) exhibited an inverse relationship with CKD risk, while Glucokinase regulatory protein (GCKR) showed an increased risk of CKD. Furthermore, our colocalization analysis also supported the associations of TCEA2, NRG4, and GCKR with the risk of eGFRcrea and eGFR.
Insights
This study identifies three proteins linked to chronic kidney disease (CKD) risk using genetic analysis. Transcription elongation factor A protein 2 (TCEA2) and Neuregulin-4 (NRG4) may protect against CKD, while Glucokinase regulatory protein (GCKR) is associated with increased risk.
Area of Science:
- Genetics
- Proteomics
- Nephrology
Background:
- Chronic kidney disease (CKD) poses a significant health burden, necessitating novel therapeutic targets.
- The proteome offers a rich source of potential drug discovery targets for complex diseases like CKD.
- Understanding genetic influences on protein levels is crucial for identifying causal links to disease risk.
Purpose of the Study:
- To perform proteome-wide analyses to identify potential therapeutic targets for chronic kidney disease (CKD).
- To investigate the associations between genetically predicted circulating protein levels and CKD, estimated glomerular filtration rate (eGFRcrea), and estimated glomerular filtration rate (eGFR).
- To utilize Mendelian randomization (MR) and colocalization to establish shared genetic causality between proteins and kidney function parameters.
Main Methods:
- Proteome-wide association study (PWAS) using summary-level data from the ARIC study and Icelandic cohorts.
- Mendelian randomization (MR) analysis to assess the causal effect of protein levels on CKD risk and eGFR.
- Colocalization analysis to determine if genetic variants influence both protein levels and CKD/eGFR through shared causal pathways.
Main Results:
- Identified significant genetic correlations between circulating protein levels and CKD, eGFRcrea, and eGFR.
- Genetically predicted levels of Transcription elongation factor A protein 2 (TCEA2) were inversely associated with CKD risk.
- Genetically predicted levels of Neuregulin-4 (NRG4) showed an inverse association with CKD risk, while Glucokinase regulatory protein (GCKR) was associated with increased CKD risk.
- Colocalization analysis robustly supported the shared genetic basis for TCEA2, NRG4, and GCKR with CKD, eGFRcrea, and eGFR.
Conclusions:
- TCEA2 and NRG4 represent potential protective targets for CKD drug discovery.
- GCKR may represent a therapeutic target for increasing CKD risk.
- These findings highlight the utility of integrating proteomic and genetic data for identifying novel CKD targets.
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