Plasma Proteomics of Renal Function: A Transethnic Meta-Analysis and Mendelian Randomization Study

Significance Statement Studies on the plasma proteome of renal function have identified several biomarkers, but have lacked replication, were limited to European populations, and/or did not investigate causality with eGFR. Among four cohorts in a transethnic cross-sectional study, 57 plasma proteins were associated with eGFR, 23 of them also with CKD. Furthermore, Mendelian randomization and gene expression analyses in kidney tissue highlighted testican-2 as a physiological marker of kidney disease progression with potential clinical relevance, and identified a few additional proteins warranting further investigation. 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.