Plasma Proteomics of Renal Function: A Trans-ethnic Meta-analysis and Mendelian Randomization Study

Pamela Matías-García, Rory Wilson, Qi Guo, Shaza Zaghlool, James Eales, Xiaoguang Xu, Fadi Charchar, John Dormer, Haifa Maalmi, Pascal Schlosser, Mohamed Elhadad, Jana Nano, Sapna Sharma, Annette Peters, Alessia Fornoni, Dennis Mook-Kanamori, Juliane Winkelmann, John Danesh, Emanuele Di Angelantonio, Willem OuwehandNicholas Watkins, Agnese Petrera, Johannes Graumann, Wolfgang Koenig, Kristian Hveem, Christian Jonasson, Anna Köttgen, Adam Butterworth, Marco Prunotto, Stefanie Hauck, Christian Herder, Karsten Suhre, Christian Gieger, Maciej Tomaszewski, Alexander Teumer, Melanie Waldenberger

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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.

Original languageEnglish
Pages (from-to)1747-1763
Number of pages17
JournalJournal of the American Society of Nephrology : JASN
Issue number7
Early online date30 Jun 2021
Publication statusPublished - Jul 2021


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