A novel multi-ancestry proteome-wide Mendelian randomization study implicates extracellular proteins, tubular cells, and fibroblasts in estimated glomerular filtration rate regulation

Matthew B Lanktree; Nicolas Perrot; Andrew Smyth; Michael Chong; Sukrit Narula; Meera Shanmuganathan; Zachary Kroezen; Philip Britz-Mckibbin; Mario Berger; Joan C Krepinsky; Marie Pigeyre; Salim Yusuf; Guillaume Paré

doi:10.1016/j.kint.2023.08.025

A novel multi-ancestry proteome-wide Mendelian randomization study implicates extracellular proteins, tubular cells, and fibroblasts in estimated glomerular filtration rate regulation

Kidney Int. 2023 Dec;104(6):1170-1184. doi: 10.1016/j.kint.2023.08.025. Epub 2023 Sep 27.

Authors

Affiliations

¹ Population Health Research Institute, Hamilton, Ontario, Canada; Division of Nephrology, St. Joseph's Healthcare Hamilton, Hamilton, Ontario, Canada; Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada; Department of Medicine, McMaster University, Hamilton, Ontario, Canada. Electronic address: lanktree@mcmaster.ca.
² Population Health Research Institute, Hamilton, Ontario, Canada.
³ Population Health Research Institute, Hamilton, Ontario, Canada; HRB Clinical Research Facility Galway, University of Galway, Galway, Ireland.
⁴ Population Health Research Institute, Hamilton, Ontario, Canada; Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
⁵ Department of Chemistry and Chemical Biology, McMaster University, Hamilton, Ontario, Canada.
⁶ Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada; Department of Chemistry and Chemical Biology, McMaster University, Hamilton, Ontario, Canada.
⁷ Bayer AG, Pharmaceuticals Research & Development, Pharma Research Center, Wuppertal, Germany.
⁸ Division of Nephrology, St. Joseph's Healthcare Hamilton, Hamilton, Ontario, Canada; Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
⁹ Population Health Research Institute, Hamilton, Ontario, Canada; Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
¹⁰ Population Health Research Institute, Hamilton, Ontario, Canada; Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada; Department of Medicine, McMaster University, Hamilton, Ontario, Canada; Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.

PMID: 37774922
DOI: 10.1016/j.kint.2023.08.025

Abstract

Estimated glomerular filtration rate (eGFR) impacts the concentration of plasma biomarkers confounding biomarker association studies of eGFR with reverse causation. To identify biomarkers causally associated with eGFR, we performed a proteome-wide Mendelian randomization study. Genetic variants nearby biomarker coding genes were tested for association with plasma concentration of 1,161 biomarkers in a multi-ancestry sample of 12,066 participants from the Prospective Urban and Rural Epidemiological (PURE) study. Using two-sample Mendelian randomization, individual variants' effects on biomarker concentration were correlated with their effects on eGFR and kidney traits from published genome-wide association studies (GWAS). Genetically altered concentrations of 22 biomarkers were associated with eGFR above a Bonferroni-corrected significance threshold. Five biomarkers were previously identified by GWAS (UMOD, FGF5, LGALS7, NINJ1, COL18A1). Nine biomarkers were within 1 Mb of the lead GWAS variant but the gene for the biomarker was unidentified as the candidate for the GWAS signal (INHBC, TNFRSF11A, TCN2, PXN1, PRTN3, PSMD9, TFPI, ITGB6, CA3). Single-cell transcriptomic data indicated the 22 biomarkers are expressed in kidney tubules, collecting duct, fibroblasts, and immune cells. Pathway analysis showed significant enrichment of identified biomarkers in the extracellular kidney parenchyma. Thus, using genetic regulators of biomarker concentration via proteome-wide Mendelian randomization, we identified 22 biomarkers that appear to causally impact eGFR in either a beneficial or adverse manner. The current study provides rationale for novel therapeutic targets for eGFR and emphasized a role for extracellular proteins produced by tubular cells and fibroblasts for impacting eGFR.

Keywords: Mendelian randomization; chronic kidney disease; genomics.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Biomarkers
Cell Adhesion Molecules, Neuronal
Fibroblasts
Genome-Wide Association Study*
Glomerular Filtration Rate / genetics
Humans
Mendelian Randomization Analysis
Nerve Growth Factors
Prospective Studies
Proteasome Endopeptidase Complex
Proteome*

Substances

Proteome
Biomarkers
PSMD9 protein, human
Proteasome Endopeptidase Complex
NINJ1 protein, human
Nerve Growth Factors
Cell Adhesion Molecules, Neuronal

Abstract

Publication types

MeSH terms

Substances

Grants and funding