Plasma proteomics of renal function: A transethnic meta-analysis and mendelian randomization study

- Matías-García, Pamela, Wilson, Rory, Guo, Qi, Zaghlool, Shaza, Charchar, Fadi

Title
Plasma proteomics of renal function: A transethnic meta-analysis and mendelian randomization study
Creator
Matías-García, Pamela; Wilson, Rory; Guo, Qi; Zaghlool, Shaza; Charchar, Fadi
Date
2021
Type
Text; Journal article
Identifier
http://researchonline.federation.edu.au/vital/access/HandleResolver/1959.17/179706
Identifier
vital:15660
Identifier
https://doi.org/10.1681/ASN.2020071070
Identifier
ISBN:1046-6673 (ISSN)
Abstract
Background Studies on the relationship between renal function and the human plasma proteome have identified several potential biomarkers. However, investigations have been conducted largely in European populations, and causality of the associations between plasma proteins and kidney function has never been addressed. Methods A cross-sectional study of 993 plasma proteins among 2882 participants in four studies of European and admixed ancestries (KORA, INTERVAL, HUNT, QMDiab) identified transethnic associations between eGFR/CKD and proteomic biomarkers. For the replicated associations, two-sample bidirectional Mendelian randomization (MR) was used to investigate potential causal relationships. Publicly available datasets and transcriptomic data from independent studies were used to examine the association between gene expression in kidney tissue and eGFR. Results In total, 57 plasma proteins were associated with eGFR, including one novel protein. Of these, 23 were additionally associated with CKD. The strongest inferred causal effect was the positive effect of eGFR on testican-2, in line with the known biological role of this protein and the expression of its protein-coding gene (SPOCK2) in renal tissue. We also observed suggestive evidence of an effect of melanoma inhibitory activity (MIA), carbonic anhydrase III, and cystatin-M on eGFR. Conclusions In a discovery-replication setting, we identified 57 proteins transethnically associated with eGFR. The revealed causal relationships are an important stepping stone in establishing testican-2 as a clinically relevant physiological marker of kidney disease progression, and point to additional proteins warranting further investigation. © 2021 by the American Society of Nephrology
Publisher
American Society of Nephrology
Relation
Journal of the American Society of Nephrology Vol. 32, no. 7 (2021), p. 1747-1763
Rights
All metadata describing materials held in, or linked to, the repository is freely available under a CC0 licence
Rights
http://creativecommons.org/licenses/by/3.0/
Rights
Copyright © 2021 by the American Society of Nephrology
Rights
Open Access
Subject
1103 Clinical Sciences
Full Text
Reviewed
Funder
The KORA study was initiated and financed by the Helmholtz Zentrum Mu€nchen German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research and the State of Bavaria. This work was also supported by Weill Cornell Medicine in Qatar Biomedical Research Program, the Qatar Foundation, and Qatar National Research Fund grant NPRPC11-0115-180010 (to K. Suhre). The HUNT Study is a collaboration between HUNT Research Centre (Norwegian University of Science and Technology), Nord-Trøndelag County Council, Central Norway Health Authority, and the Norwegian Institute of Public Health. J. Danesh is supported by the National Institute for Health Research Senior Investigator Award. RNA-sequencing experiments and kidney gene expression studies were supported by British Heart Foundation project grants PG/17/35/33001 and PG/19/16/34270, and Kidney Research UK grants RP_017_20180302 and RP_013_20190305 (to M. Tomaszewski). The German Diabetes Center is funded by the German Federal Ministry of Health (Berlin, Germany), the Ministry of Culture and Science of the state North Rhine-Westphalia (Du€sseldorf, Germany), and grants from the German Federal Ministry of Education and Research (Berlin, Germany) to the German Center for Diabetes Research. The work of A. Ko€ttgen is supported by he Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) – Project-ID 431984000 – SFB 1453.
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