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Updated: May 29, 2025

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Pyruvate and Related Energetic Metabolites Modulate Resilience Against High Genetic Risk for Glaucoma.

Keva Li1, Nicholas Tolman2, Ayellet V Segrè3,4

  • 1Department of Ophthalmology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

Biorxiv : the Preprint Server for Biology
|February 3, 2025
PubMed
Summary
This summary is machine-generated.

Glaucoma risk can be identified using a polygenic risk score (PRS), but some high-risk individuals remain resilient. Metabolites, particularly pyruvate, show a protective effect, suggesting new therapeutic targets for glaucoma prevention.

Keywords:
genetic risk scoregeneticsglaucomaglaucoma resilienceglycolysismetabolite risk scoremetabolitespyruvatetricarboxylic acid cycle

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Area of Science:

  • Ophthalmology
  • Metabolomics
  • Genetics

Background:

  • Glaucoma polygenic risk scores (PRS) identify disease susceptibility.
  • However, not all individuals with high PRS develop glaucoma, indicating resilience factors.
  • Understanding these resilience mechanisms is crucial for effective glaucoma management.

Purpose of the Study:

  • To investigate if plasma metabolites improve glaucoma prediction.
  • To identify a metabolomic signature of resilience in individuals with high genetic glaucoma risk.
  • To validate the role of specific metabolites in a mouse model of glaucoma.

Main Methods:

  • Cross-sectional study of 4,658 glaucoma cases and 113,040 controls from the UK Biobank.
  • Logistic regression models incorporating 168 NMR-based metabolites and PRS.
  • Experimental validation using a mouse model (Mus musculus) with dietary pyruvate.

Main Results:

  • Metabolites alone weakly predicted glaucoma (AUC=0.579) but marginally improved PRS models.
  • A resilience signature in high PRS individuals included elevated glycolysis metabolites: lactate, pyruvate, and citrate.
  • Dietary pyruvate reduced intraocular pressure and optic nerve damage in a mouse glaucoma model.

Conclusions:

  • Plasma metabolites, particularly those related to glycolysis and pyruvate metabolism, are associated with resilience to glaucoma.
  • Pyruvate shows a protective effect against glaucoma pathogenesis, evidenced in both human data and a mouse model.
  • These findings suggest potential therapeutic strategies targeting metabolic pathways for glaucoma prevention and treatment.