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Abstract: FR-PO371

Genetic Studies of Paired Metabolomes Reveal Enzymatic and Transport Processes at the Interface of Plasma and Urine

Session Information

Category: Genetic Diseases of the Kidneys

  • 1102 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • Schlosser, Pascal, Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany
  • Scherer, Nora, Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany
  • Grundner-Culemann, Franziska, Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany
  • Li, Yong, Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany
  • Kottgen, Anna, Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany
Background

The kidneys operate at the interface of plasma and urine by clearing molecular waste products from the body while retaining valuable solutes. We hypothesized that a genetic study of paired plasma and urine metabolomes facilitates the identification of transport proteins and enzymes involved in this process.

Methods

We performed genome-wide association studies of 1,916 metabolites, of which 779 were quantified in plasma and urine from 5,023 participants of the German Chronic Kidney Disease study. Identified associations were integrated with orthogonal datasets, including colocalization with expression and protein quantitative trait loci to prioritize the underlying genes, and with complex traits and diseases to identify potential consequences. ATAC- and RNA-seq data from primary human kidney was used to annotate regulatory variants.

Results

We found 1,299 significant associations between genetic variants and metabolite levels, including examples related to the kidneys’ role in metabolite handling. Of note, studying either plasma or urine alone would have missed associations with 40% of the underlying metabolites. The major genes and metabolite pathways shaping the plasma and the urine associations were clearly distinct. Insights only enabled through the study of urine included the identification of a missense variant in AQP7 resulting in reduced tubular glycerol reabsorption. The kidney-enriched transporter SLC13A3 left different metabolomic footprints in plasma and urine, consistent with its function in mitochondrial energy generation. The prioritized underlying variant is predicted to specifically alter binding of major cell type-relevant transcription factors. Shared genetic determinants of 7,515 metabolite-biomarker/disease combinations provided mechanistic hypotheses for complex and monogenic diseases and allowed for the characterization of yet undescribed systemic roles of renal dipeptidase 1.

Conclusion

This genetic study of plasma and urine metabolomes emphasizes the role of multi-matrix studies to gain insights into in vivometabolic processes, and particularly into kidney functions. The results provide a rich resource of yet unknown enzymatic and transport processes that represent a molecular link to human diseases.

Funding

  • Commercial Support