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

Area of Science:

• Proteomics
• Nephrology
• Human Genetics

Background:

• Previous studies linked plasma proteome to renal function but lacked diversity and causality.
• Investigations were primarily conducted in European populations.
• Causality of plasma protein associations with kidney function remained unaddressed.

Purpose of the Study:

• To identify transethnic associations between plasma proteins and kidney function (eGFR/CKD).
• To investigate potential causal relationships between identified proteins and kidney function using Mendelian randomization.
• To explore the role of kidney tissue gene expression in eGFR.

Main Methods:

• Cross-sectional study of 993 plasma proteins in 2882 participants from four studies.
• Two-sample bidirectional Mendelian randomization (MR) for causal inference.
• Analysis of publicly available datasets and kidney tissue transcriptomic data.

Main Results:

• 57 plasma proteins associated with eGFR, including one novel protein; 23 also associated with CKD.
• Strongest causal effect: positive association between eGFR and testican-2.
• Suggestive evidence for associations of MIA, carbonic anhydrase III, and cystatin-M with eGFR.

Conclusions:

• Identified 57 plasma proteins transethnically associated with eGFR in a discovery-replication setting.
• Established testican-2 as a potential physiological marker for kidney disease progression.
• Highlighted additional proteins for future kidney disease research.