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January 22nd, 2025

Version: 1

Icahn School of Medicine at Mount Sinai

genomics

biorxiv

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

Li, K.Open in Google Scholar•Tolman, N.Open in Google Scholar•V. Segre, A.Open in Google Scholar•Stuart, K.Open in Google Scholar•Zeleznik, O. A.Open in Google Scholar•Vallabh, N. A.Open in Google Scholar•Hu, K.Open in Google Scholar•Zebardast, N.Open in Google Scholar•Hanyuda, A.Open in Google Scholar•Raita, Y.Open in Google Scholaret al.

Glaucoma polygenic risk scores (PRS) effectively identify disease risk, but some individuals with high PRS do not develop glaucoma. Factors contributing to this resilience remain unclear. Using 4,658 glaucoma cases and 113,040 controls in a cross-sectional study in the UK Biobank, we investigated whether plasma metabolites enhanced glaucoma prediction and if a metabolomic signature of resilience in high-genetic risk individuals existed. Logistic regression models incorporating 168 NMR-based metabolites into PRS-based glaucoma assessments were developed, with multiple comparison corrections applied. While metabolites weakly predicted glaucoma (Area Under the Curve=0.579), they offered modest prediction improvement in PRS-only-based models (P=0.004). We identified a metabolomic signature associated with resilience in the top PRS decile, with elevated glycolysis-related metabolites-lactate (P=8.8E-12), pyruvate (P=1.9E-10), and citrate (P=0.02)-linked to reduced glaucoma prevalence. These metabolites combined significantly modified the PRS-glaucoma relationship (Pinteraction=0.011). Higher total resilience metabolite levels within the highest PRS quartile corresponded to lower glaucoma prevalence (Odds Ratiohighest vs. lowest total resilience metabolite quartile=0.71, 95% Confidence Interval [CI]=0.64-0.80). As pyruvate is a foundational metabolite linking glycolysis to tricarboxylic acid cycle metabolism and ATP generation, we pursued experimental validation for this putative resilience biomarker in a human-relevant Mus musculus glaucoma model. Dietary pyruvate mitigated elevated intraocular pressure (P=0.002) and optic nerve damage (P<0.0003) in Lmx1bV265D mice. These findings highlight the protective role of pyruvate-related metabolism against glaucoma and suggest potential avenues for therapeutic intervention.

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