Abstract: TH-OR034
Integrative Proteome- and Phenome-Wide Study Uncovers Causal Protein Drivers and Drug Targets for Kidney Disease Subtypes
Session Information
- Genetics of Complex Kidney Traits
November 06, 2025 | Location: Room 360A, Convention Center
Abstract Time: 05:30 PM - 05:40 PM
Category: Genetic Diseases of the Kidneys
- 1202 Genetic Diseases of the Kidneys: Complex Kidney Traits
Authors
- Triozzi, Jefferson Lorenzo, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Mamak, Fatih, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Tao, Ran, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Pereira, Alexandre Costa, Harvard Medical School, Boston, Massachusetts, United States
- Hung, Adriana, Vanderbilt University Medical Center, Nashville, Tennessee, United States
Background
Large-scale drug-target proteomics studies for kidney disease often rely on cross-sectional assessments and ignore extra-renal pleiotropy. We implemented a proteome-to-phenome pipeline based on longitudinal health records that links causal protein drivers and their drug targets to discrete kidney disease subtypes while exposing their systemic effects.
Methods
Using cis-acting plasma protein quantitative-trait loci for 2,478 circulating proteins, we performed two-sample Mendelian randomization (MR) against a composite kidney-function trait integrating baseline eGFR, incident chronic kidney disease, end-stage kidney disease, and annualized eGFR slope estimated using linear mixed-effects modeling from 464,631 Veterans Affairs Million Veteran Program (MVP) participants. We mapped targets to subtypes based on GWAS meta-analyses of the MVP, UK Biobank, and FinnGen. Candidate proteins were evaluated using phenome-wide association studies (PheWAS) and the renal effects of drugs targeting these proteins were interpreted in this context.
Results
We identified 118 proteins with experiment-wide significance. Targeted MR across 10 kidney disease subtypes mapped them to distinct clinical contexts (such as GCKR, APOE diabetic nephropathy, ANGPTL3 glomerular diseases, DPEP1 acute renal failure, IL1RN microscopic hematuria). PheWAS uncovered pleiotropic signals, flagging potential safety liabilities, and network-based druggability screens prioritized 32 actionable pathways.
Conclusion
This proteome-to-phenome screen integrated genetic determinants of circulating proteins, their effects on a comprehensive kidney function outcome, and identifies associated disease subtypes and systemic effects. This delivered a catalogue of therapeutic axes and safety signals.
Funding
- Veterans Affairs Support