---
title: "INHBC and other protein mediators linking Type 2 diabetes to chronic kidney disease: Mendelian ran"
id: "plos-medicine-1-protein-mediators-of-chronic-kidney-disease-in-type-2-diabetes-a-mendelian"
canonical_url: "https://medichelpline.com/clinical-feed/plos-medicine-1-protein-mediators-of-chronic-kidney-disease-in-type-2-diabetes-a-mendelian"
content_type: "clinical_feed_article"
specialty: "Nephrology"
source_name: "PLOS Medicine"
source_url: "https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1004802"
published_at: "2026-09-11T14:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# INHBC and other protein mediators linking Type 2 diabetes to chronic kidney disease: Mendelian ran
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/plos-medicine-1-protein-mediators-of-chronic-kidney-disease-in-type-2-diabetes-a-mendelian
- **Specialty:** [Nephrology](https://medichelpline.com/clinical-feed/nephrology.md)
- **Primary Source:** PLOS Medicine
- **Source URL:** [Original Journal Publication](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1004802)
- **Published At:** 2026-09-11T14:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- This study used large-scale proteomic and genetic data to identify circulating proteins that mediate the effect of **Type 2 diabetes** (T2D) on kidney outcomes using a two-sample **Mendelian randomization** (MR) framework. - An initial MR screen found 71 circulating proteins whose levels were altered by genetic liability to T2D, using proteomic GWAS from deCODE (35,559 individuals) and a T2D GWAS with 80,154 cases. - Using cis-genetic instruments to proxy protein effects, five proteins (INHBC, GNPTG, LPO, AGRN, CTSD) were identified as influencing three kidney traits: **blood urea nitrogen** (BUN), **estimated glomerular filtration rate** (eGFR) and chronic kidney disease (CKD) risk in GWAS of up to 1,004,040 participants. - Higher circulating **INHBC** was estimated by MR to causally lower eGFR and raise BUN; observational analyses in 37,854 UK Biobank participants also showed higher INHBC associated with increased hazard of a kidney disease diagnosis. - Replication using proteomic GWAS from four additional cohorts (UKB-PPP, Fenland, ARIC, EPIC-Norfolk) showed consistent direction of effect across platforms and cohorts, supporting robustness to assay and cohort variation. - In mediation analysis, circulating INHBC levels were estimated to mediate 1.3% (95% CI 0.85%–1.9%) of the association between T2D and kidney disease diagnosis. - The authors note important limitations: some MR assumptions are untestable; analyses used population-based GWAS for T2D and kidney traits rather than cohorts of individuals with diabetic kidney disease specifically; and functional validation in disease-specific cohorts is needed. - Overall, findings suggest that T2D may increase CKD risk in part through higher circulating **INHBC**, and five proteins warrant further study as potential mediators or therapeutic targets.
## Clinical Analysis & Structured Key Points
[ Skip to main content ](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1004802#main-content) Advertisement * [plos.org](https://plos.org/) * [Create account](https://community.plos.org/registration/new) * [Sign in](https://journals.plos.org/user/secure/login?page=%2Fplosmedicine%2Farticle%3Fid%3D10.1371%2Fjournal.pmed.1004802) * * About * Browse * Publish * [](https://journals.plos.org/plosmedicine/ "PLOS Medicine") * Search [advanced search](https://journals.plos.org/plosmedicine/search) * 0 [Save](https://journals.plos.org/plosmedicine/article/metrics?id=10.1371/journal.pmed.1004802#savedHeader) [Total Mendeley and Citeulike bookmarks.](https://journals.plos.org/plosmedicine/article/metrics?id=10.1371/journal.pmed.1004802#savedHeader) * 0 [Citation](https://journals.plos.org/plosmedicine/article/metrics?id=10.1371/journal.pmed.1004802#citedHeader) [Paper's citation count computed by Dimensions.](https://journals.plos.org/plosmedicine/article/metrics?id=10.1371/journal.pmed.1004802#citedHeader) * 12 [View](https://journals.plos.org/plosmedicine/article/metrics?id=10.1371/journal.pmed.1004802#viewedHeader) [PLOS views and downloads.](https://journals.plos.org/plosmedicine/article/metrics?id=10.1371/journal.pmed.1004802#viewedHeader) * 0 [Share](https://journals.plos.org/plosmedicine/article/metrics?id=10.1371/journal.pmed.1004802#discussedHeader) [Sum of Facebook, Twitter, Reddit and Wikipedia activity.](https://journals.plos.org/plosmedicine/article/metrics?id=10.1371/journal.pmed.1004802#discussedHeader) Open Access Peer-reviewed Research Article # Protein mediators of chronic kidney disease in Type 2 diabetes: A mendelian randomization study * Kevin Y. H. Liang, Roles Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Validation, Visualization, Writing – original draft, Writing – review & editing Affiliations Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, Québec, Canada, 5 Prime Sciences Inc, Montréal, Québec, Canada [ ![ORCID logo](https://journals.plos.org/resource/img/orcid_16x16.png) https://orcid.org/0000-0003-3268-0058 ](https://orcid.org/0000-0003-3268-0058 "ORCID Registry") ⨯ * Thomas M. Zheng, Roles Writing – review & editing Affiliations Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, Québec, Canada, Quantitative Life Sciences, McGill University, Montréal, Québec, Canada [ ![ORCID logo](https://journals.plos.org/resource/img/orcid_16x16.png) https://orcid.org/0009-0005-9674-5991 ](https://orcid.org/0009-0005-9674-5991 "ORCID Registry") ⨯ * Dandan Tan, Roles Writing – review & editing Affiliations Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, Québec, Canada, Quantitative Life Sciences, McGill University, Montréal, Québec, Canada ⨯ * Takayoshi Sasako, Roles Methodology, Writing – review & editing Affiliations Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, Québec, Canada, Tanaka Diabetes Clinic Omiya, Omiya, Saitama, Japan, Okachimachi Ohisama Clinic, Tokyo, Japan, Department of Diabetes, Metabolism and Endocrinology, Ichikawa Medical Center, International University of Health and Welfare, Ichikawa, Chiba, Japan ⨯ * Yann Ilboudo, Roles Supervision, Writing – review & editing Affiliations Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, United States of America, Harvard Medical School, Boston, Massachusetts, United States of America ⨯ * Yiheng Chen, Roles Methodology, Writing – review & editing Affiliation Precision Healthcare University Research Institute (PHURI), Queen Mary University of London, London, United Kingdom ⨯ * Guillaume Butler-Laporte, Roles Methodology, Writing – review & editing Affiliations Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, Québec, Canada, Centre for Human Genetics, University of Oxford, Oxford, United Kingdom, Division of Infectious Diseases, McGill University Health Centre, Montréal, Québec, Canada [ ![ORCID logo](https://journals.plos.org/resource/img/orcid_16x16.png) https://orcid.org/0000-0001-5388-0396 ](https://orcid.org/0000-0001-5388-0396 "ORCID Registry") ⨯ * Satoshi Yoshiji, Roles Methodology, Writing – review & editing Affiliations Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, Québec, Canada, Department of Human Genetics, McGill University, Montréal, Québec, Canada, Programs in Metabolism and Medical & Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America [ ![ORCID logo](https://journals.plos.org/resource/img/orcid_16x16.png) https://orcid.org/0000-0001-8863-2413 ](https://orcid.org/0000-0001-8863-2413 "ORCID Registry") ⨯ * J. Brent Richards Roles Conceptualization, Funding acquisition, Resources, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing * E-mail: brent.richards@mcgill.ca Affiliations Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, Québec, Canada, 5 Prime Sciences Inc, Montréal, Québec, Canada, Department of Human Genetics, McGill University, Montréal, Québec, Canada, Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montréal, Québec, Canada, Department of Twin Research, King’s College London, London, United Kingdom, Department of Medicine, McGill University, Montréal, Quebec, Canada [ ![ORCID logo](https://journals.plos.org/resource/img/orcid_16x16.png) https://orcid.org/0000-0002-3746-9086 ](https://orcid.org/0000-0002-3746-9086 "ORCID Registry") ⨯ # Protein mediators of chronic kidney disease in Type 2 diabetes: A mendelian randomization study * Kevin Y. H. Liang, * Thomas M. Zheng, * Dandan Tan, * Takayoshi Sasako, * Yann Ilboudo, * Yiheng Chen, * Guillaume Butler-Laporte, … * Satoshi Yoshiji, * J. Brent Richards ![PLOS](https://journals.plos.org/resource/img/logo-plos-full-color.svg) x * Published: September 11, 2026 * * [Article](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1004802) * [Authors](https://journals.plos.org/plosmedicine/article/authors?id=10.1371/journal.pmed.1004802) * [Metrics](https://journals.plos.org/plosmedicine/article/metrics?id=10.1371/journal.pmed.1004802) * [Comments](https://journals.plos.org/plosmedicine/article/comments?id=10.1371/journal.pmed.1004802) * [Media Coverage](http://plos.altmetric.com/details/doi/10.1371/journal.pmed.1004802) * [Abstract](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1004802#abstract0) * [Author summary](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1004802#abstract1) * [1 Introduction](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1004802#sec004) * [2 Methods](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1004802#sec005) * [3 Results](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1004802#sec028) * [4 Discussion](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1004802#sec041) * [Supporting information](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1004802#sec042) * [Acknowledgments](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1004802#ack) * [References](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1004802#references) * [Reader Comments](https://journals.plos.org/plosmedicine/article/comments?id=10.1371/journal.pmed.1004802) * [Figures](https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1004802) ## 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. ## Author summary ### Why was this study done? * Individuals living with diabetes are at an increased risk of developing kidney diseases; however, it is not clear how T2D causes kidney function decline, and more importantly, why this develops in some individuals but not others. * A better understanding of the pathophysiology of this disease will help develop better therapeutics and improve risk prediction. * We hypothesize that T2D-mediated changes in the proteome contributes to kidney function decline. ### What did the researchers do and find? * We leverage population-level genetic association studies to identify potential protein mediators between T2D on kidney diseases. * We identified 5 proteins whose levels were changed by T2D susceptibility that in turn affect kidney function. * Notably, T2D susceptibility was associated with an increase in circulating inhibin beta C-chain level (INHBC), a member of the TGF-![](https://journals.plos.org/plosmedicine/article/file?type=thumbnail&id=10.1371/journal.pmed.1004802.e001) signaling pathway with known roles in tissue fibrosis. ### What do these findings mean? * We identified 5 proteins (NHBC, GNPTG, LPO, AGRN, and CTSD), whose circulating levels were altered by genetic susceptibility to T2D which in turn affected three kidney traits (BUN, eGFR, and CKD risk). * Follow-up analyses suggest that T2D may impair kidney function partly through up-• regulating INHBC levels. * However, there are important limitations to this study. Namely, this study infers protein mediators between T2D and kidney disease using disease-specific GWAS for T2D and kidney function measurements and not diabetic kidney disease specifically; therefore, follow-up studies on a diabetic kidney disease-specific cohort are needed for validation of the findings in this study. ## Figures ![Fig 4](https://journals.plos.org/plosmedicine/article/figure/image?size=inline&id=10.1371/journal.pmed.1004802.g004) ![Fig 5](https://journals.plos.org/plosmedicine/article/figure/image?size=inline&id=10.1371/journal.pmed.1004802.g005) ![Fig 6](https://journals.plos.org/plosmedicine/article/figure/image?size=inline&id=10.1371/journal.pmed.1004802.g006) ![Fig 1](https://journals.plos.org/plosmedicine/article/figure/image?size=inline&id=10.1371/journal.pmed.1004802.g001) ![Fig 2](https://journals.plos.org/plosmedicine/article/figure/image?size=inline&id=10.1371/journal.pmed.1004802.g002) ![Fig 3](https://journals.plos.org/plosmedicine/article/figure/image?size=inline&id=10.1371/journal.pmed.1004802.g003) ![Fig 4](https://journals.plos.org/plosmedicine/article/figure/image?size=inline&id=10.1371/journal.pmed.1004802.g004) ![Fig 5](https://journals.plos.org/plosmedicine/article/figure/image?size=inline&id=10.1371/journal.pmed.1004802.g005) ![Fig 6](https://journals.plos.org/plosmedicine/article/figure/image?size=inline&id=10.1371/journal.pmed.1004802.g006) ![Fig 1](https://journals.plos.org/plosmedicine/article/figure/image?size=inline&id=10.1371/journal.pmed.1004802.g001) ![Fig 2](https://journals.plos.org/plosmedicine/article/figure/image?size=inline&id=10.1371/journal.pmed.1004802.g002) ![Fig 3](https://journals.plos.org/plosmedicine/article/figure/image?size=inline&id=10.1371/journal.pmed.1004802.g003) **Citation:** Liang KYH, Zheng TM, Tan D, Sasako T, Ilboudo Y, Chen Y, et al. (2026) Protein mediators of chronic kidney disease in Type 2 diabetes: A mendelian randomization study. PLoS Med 23(9): e1004802. https://doi.org/10.1371/journal.pmed.1004802 **Academic Editor:** Weiping Jia, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, CHINA **Received:** July 11, 2025; **Accepted:** August 4, 2026; **Published:** September 11, 2026 **Copyright:** © 2026 Liang et al. This is an open access article distributed under the terms of the [Creative Commons Attribution License](http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. **Data Availability:** UK Biobank data are available after successful application through the appropriate application portal ( ). Sources for GWAS summary statistics used in this study are listed in Supplementary Table S1. Codes are deposited on GitHub ( , ). All analyses are conducted in R 4.1.2 or Python 3.10.9. GTEx data used in this study are publicly available on ([https://gtexportal.org/home/)](https://gtexportal.org/home/) and were obtained from the GTEx Portal on MAR/07/2024. **Funding:** The Richards research group is supported by the Tri-agency Institutional Programs Secretariat (TIPS Program to JBR), CQDM (MEIE: to JBR) and Hoffmann-La Roche Limited ( to JBR), the Canadian Institutes of Health Research ( ) [grant numbers: 365825; 409511, 100558, and 169303 to JBR], the McGill Interdisciplinary Initiative in Infection and Immunity (MI4, to JBR), the Lady Davis Institute of the Jewish General Hospital ( to JBR), the Jewish General Hospital Foundation ( to JBR), the Canadian Foundation for Innovation ( to JBR), the NIH Foundation ( to JBR), Genome Québec ( to JBR), the Public Health Agency of Canada ( to JBR), McGill University ( to JBR), Cancer Research UK ( ) [grant numbers: C18281/A29019 to JBR)] and the Fonds de Recherche Québec Santé (FRQS, to JBR). JBR is supported by a FRQS Mérite Clinical Research Scholarship ( to JBR) and Canada Research Chairs Program (CRCP, to JBR) Tier 1. Support from Calcul Québec ( to JBR) and Compute Canada ( to JBR) is acknowledged. TwinsUK is funded by the Welcome Trust, Medical Research Council, European Union, the National Institute for Health Research (NIHR)-funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust in partnership with King’s College London. KYHL was supported by CIHR Institute of Cancer Research doctoral research award ( ) [grant numbers: 181613 to KYHL]. DT is supported by FRQS ( ) doctoral scholarship [DOI: to DT]. TS is supported by the Medical Research Encouragement Prize of The Japan Medical Association ( ) and the Fund for the Promotion of Joint International Research (Fostering Joint International Research) [grant number: 23KK0301 to TS] by the Japan Society for the Promotion of Science ( ). TMZ received support from the Canada First Research Excellence Fund awarded to the D2R Initiative at McGill University ( ) [grant number: CFREF-2022-00045 to TMZ). GBL received support from FRQS [ to GBL]. YI is supported through the Canada Postdoctoral Research Award (CPRA) program from the Canadian Institute of Health [grant number: 208352 to YI]. SY is supported by the Canada Research Chairs Program ( ) [grant number: CRC-2025-00097 to SY], the Canadian Institutes of Health Research ( ) [grant number: 183596 to SY], and the DNA to RNA (D2R) Foundational Program. The funders had no role in study design, data collection and analysis, decision to publish, preparation of the manuscript, or interpretation of the study. **Competing interests:** I have read the journal’s policy, and the authors of this manuscript have the following competing interests: JBR’s institution has received investigator-initiated grant funding from Eli Lilly, GlaxoSmithKline and Biogen for projects unrelated to this research. JBR is the CEO of 5 Prime Sciences ([www.5primesciences.com](https://www.5primesciences.com)), which provides research services for biotech, pharma and venture capital companies for projects unrelated to this research. YC was an employee of 5 Prime Sciences. KYHL is an employee of 5 Prime Sciences. SY serves as a consultant to the Broad Institute of MIT and Harvard through Precision Global Consulting and to PriveBio, Inc., unrelated to this project. No conflicts of interest are declared for the other authors. **Abbreviations:** AICc, Akaike information criterion; ARIC, Atherosclerosis Risk in Communities; BMI, body mass index; BUN, blood urea nitrogen; CKD, chronic kidney disease; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; COVID-19, Coronavirus disease 2019; eGFR, glomerular filtration rate; EPIC, European Prospective Investigation of Cancer; GWAS, genome-wide association studies; GTEx, Genotype-Tissue Expression; ICD-10, International Classification of Diseases 10th revision; INHBC, inhibin beta C-chain level; KM, Kaplan-Meier; LD, linkage disequilibrium; MR, Mendelian randomization; MVMR, multivariable MR;; OPCS-4, Office of Population Censuses and Surveys Classification of Interventions and Procedures version 4; pQTL, Protein quant
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