Protein mediators of chronic kidney disease in Type 2 diabetes: A mendelian randomization study
9 affiliations
- 1Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, Québec, Canada
- 25 Prime Sciences Inc, Montréal, Québec, Canada
- 3Quantitative Life Sciences, McGill University, Montréal, Québec, Canada
- 4Tanaka Diabetes Clinic Omiya, Omiya, Saitama, Japan
- 5Okachimachi Ohisama Clinic, Tokyo, Japan
- 6Department of Diabetes, Metabolism and Endocrinology, Ichikawa Medical Center, International University of Health and Welfare, Ichikawa, Chiba, Japan
- 7Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, United States of America
- 8Harvard Medical School, Boston, Massachusetts, United States of America
- 9Precision Healthcare University Research Institute (PHURI), Queen Mary University of London, London, United Kingdom
Abstract
Background: Chronic kidney disease (CKD) occurs in 20–50% of the people living with Type 2 diabetes (T2D) and is the leading cause of kidney failure worldwide. The cause of CKD is not fully understood, and few interventions prevent CKD in individuals living with diabetes. Here, we use large-scale proteomics data to identify circulating proteins that mediate the relationship between T2D and kidney disorders. Methods and findings: First, we used two-sample mendelian randomization (MR) and identified 71 circulating proteins whose levels were altered by genetic predisposition to T2D based on circulating proteomic GWAS from deCODE with 35,559 individuals and T2D GWAS with 80,154 cases. Then, we used cis-genetic variants to proxy the causal effect of some of these T2D-influenced circulating proteins and found that, collectively, five proteins (INHBC, GNPTG, LPO, AGRN, and CTSD) affected three kidney traits (blood urea nitrogen [BUN], estimated glomerular filtration rate [eGFR] and CKD risk) based on GWAS with up to 1,004,040 participants. Notably, we found that higher levels of circulating INHBC protein were estimated to lead to a lower eGFR and higher BUN based on MR analyses. We then replicated this MR analysis with proteomic GWAS from four additional cohorts, namely, UKB-PPP, Fenland, ARIC, and EPIC-Norfolk. We observed a consistent direction of effect across all four proteomic GWAS datasets, supporting the robustness of our results against platform and cohort variation. In observational analyses, increased circulating INHBC levels were associated with increased hazard for kidney disease diagnosis in 37,854 UK Biobank participants. We estimated that circulating INHBC levels mediate 1.3% (95% confidence interval [0.85%, 1.9%]) of the association between T2D and kidney disease diagnosis. There are important limitations in this study. Firstly, although we observed limited evidence for violations to the MR assumptions, some are untestable. Secondly, our study was not based on individuals with diabetic kidney diseases, but rather independent population-based studies assessing diabetes and kidney function separately. Therefore, additional functional analyses in disease specific cohort are needed. Conclusions: Collectively, these findings suggest that T2D influences the risk of CKD, in part, through increased circulating INHBC levels. Why was this study done?: What did the researchers do and find?: What do these findings mean?: Kevin Liang and colleagues used large-scale genetic and proteomic data to explore how Type 2 diabetes may be linked to chronic kidney disease, identifying several circulating proteins associated with kidney health. Their analyses highlighted INHBC as a notable candidate.
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BibTeX
@article{liang2026protein,
title = {{Protein mediators of chronic kidney disease in Type 2 diabetes: A mendelian randomization study}},
author = {Kevin Y. H. Liang and Thomas M. Zheng and Dandan Tan and Takayoshi Sasako and Yann Ilboudo and Yiheng Chen and Guillaume Butler-Laporte and Satoshi Yoshiji and J. Brent Richards},
journal = {PLOS Medicine},
year = {2026},
month = sep,
doi = {10.1371/journal.pmed.1004802},
url = {https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1004802},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Protein mediators of chronic kidney disease in Type 2 diabetes: A mendelian randomization study
AU - Kevin Y. H. Liang
AU - Thomas M. Zheng
AU - Dandan Tan
AU - Takayoshi Sasako
AU - Yann Ilboudo
AU - Yiheng Chen
AU - Guillaume Butler-Laporte
AU - Satoshi Yoshiji
AU - J. Brent Richards
PY - 2026
DA - 2026/09/11
JO - PLOS Medicine
DO - 10.1371/journal.pmed.1004802
UR - https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1004802
AB - Background: Chronic kidney disease (CKD) occurs in 20–50% of the people living with Type 2 diabetes (T2D) and is the leading cause of kidney failure worldwide. The cause of CKD is not fully understood, and few interventions prevent CKD in individuals living with diabetes. Here, we use large-scale proteomics data to identify circulating proteins that mediate the relationship between T2D and kidney disorders. Methods and findings: First, we used two-sample mendelian randomization (MR) and identified 71 circulating proteins whose levels were altered by genetic predisposition to T2D based on circulating proteomic GWAS from deCODE with 35,559 individuals and T2D GWAS with 80,154 cases. Then, we used cis-genetic variants to proxy the causal effect of some of these T2D-influenced circulating proteins and found that, collectively, five proteins (INHBC, GNPTG, LPO, AGRN, and CTSD) affected three kidney traits (blood urea nitrogen [BUN], estimated glomerular filtration rate [eGFR] and CKD risk) based on GWAS with up to 1,004,040 participants. Notably, we found that higher levels of circulating INHBC protein were estimated to lead to a lower eGFR and higher BUN based on MR analyses. We then replicated this MR analysis with proteomic GWAS from four additional cohorts, namely, UKB-PPP, Fenland, ARIC, and EPIC-Norfolk. We observed a consistent direction of effect across all four proteomic GWAS datasets, supporting the robustness of our results against platform and cohort variation. In observational analyses, increased circulating INHBC levels were associated with increased hazard for kidney disease diagnosis in 37,854 UK Biobank participants. We estimated that circulating INHBC levels mediate 1.3% (95% confidence interval [0.85%, 1.9%]) of the association between T2D and kidney disease diagnosis. There are important limitations in this study. Firstly, although we observed limited evidence for violations to the MR assumptions, some are untestable. Secondly, our study was not based on individuals with diabetic kidney diseases, but rather independent population-based studies assessing diabetes and kidney function separately. Therefore, additional functional analyses in disease specific cohort are needed. Conclusions: Collectively, these findings suggest that T2D influences the risk of CKD, in part, through increased circulating INHBC levels. Why was this study done?: What did the researchers do and find?: What do these findings mean?: Kevin Liang and colleagues used large-scale genetic and proteomic data to explore how Type 2 diabetes may be linked to chronic kidney disease, identifying several circulating proteins associated with kidney health. Their analyses highlighted INHBC as a notable candidate.
SN - 1549-1676
ER -