Kidney Week

Abstract: FR-PO1178

Causal Effects from Kidney Function to Plasma Proteome: Integrated Observational and Mendelian Randomization Analysis with More than 50,000 UK Biobank Participants

Session Information

• CKD: Mechanisms - 2
  October 25, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

• 2303 CKD (Non-Dialysis): Mechanisms

Authors

• Cho, Jeongmin, Seoul National University College of Medicine, Jongno-gu, Seoul, Korea (the Republic of)

Jeongmin Cho, MD

• Kim, Minsang, Seoul National University Hospital, Jongno-gu, Seoul, Korea (the Republic of)

Minsang Kim

• Cho, Semin, Chung-Ang University Gwangmyeong Hospital, Gwangmyeong, Gyeonggi-do, Korea (the Republic of)

Semin Cho, MD

• Lee, Soojin, Eulji University Uijeongbu Eulji Medical Center, Uijeongbu, Gyeonggi-do, Korea (the Republic of)

Soojin Lee, MD, PhD

• Kim, Dong Ki, Seoul National University Hospital, Jongno-gu, Seoul, Korea (the Republic of)

Dong Ki Kim, MD, PhD

• Park, Sehoon, Seoul National University Hospital, Jongno-gu, Seoul, Korea (the Republic of)

Sehoon Park, MD, PhD

Background

Chronic kidney disease (CKD) causes detrimental systemic consequences leading to substantial morbidity and mortality. However, the causal effect of reduced kidney function on systemic proteomic signatures is incompletely understood. The plasma proteome is a phenotype of dynamic molecular changes within cells and tissues, providing insights into the underlying disease mechanisms and potential drug targets.

Methods

We performed an integrated Mendelian randomization (MR) and observational analysis to identify the causal association between kidney function and plasma protein levels, based on 1,815 plasma protein profiles in 50,407 UK Biobank participants and the CKDGen phase 4 GWAS meta-analysis for the genetic instruments of eGFR.

Results

The MR analysis revealed 383 plasma proteins causally associated with eGFR. Reduced kidney function was found to be causally associated with an increase in the plasma levels of 381 proteins, among which FABP1, TNF, and IGFBP4 were included, while the level of 2 proteins, NPHS1 and SPOCK1, decreased. Apoptosis-related pathway was significantly enriched in the gene-set enrichment analysis. Through the network analysis, TNF was identified as a hub protein with multiple linkages to molecules included in the TNF-signaling pathways, involved in inflammation, fibrosis, and apoptosis. In addition, the eGFR-associated proteins were annotated to molecular function GO term related to insulin-like growth factor binding.

Conclusion

In this proteo-genomic analysis, we identified 383 plasma proteins causally associated with eGFR, highlighting TNF-associated pathways as pathologically relevant processes in kidney disease progression, systemic inflammation, and organ fibrosis, warranting further investigation.