Pyruvate and related energetic metabolites modulate resilience against high genetic risk for glaucoma

A glaucoma polygenic risk score (PRS) can 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 of 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 marginal prediction improvement in PRS-only-based models (p=0.004). We identified a metabolomic signature associated with resilience in the top glaucoma 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 (P interaction = 0.011). Higher total resilience metabolite levels within the highest PRS quartile corresponded to lower glaucoma prevalence (Odds Ratio highest vs. lowest total resilience metabolite quartile =0.71, 95% Confidence Interval = 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 Lmx1b V265D mice. These findings highlight the protective role of pyruvate-related metabolism against glaucoma and suggest potential avenues for therapeutic intervention.

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Publication Details

Journal
eLife
Published
2025-04-24
DOI
https://doi.org/10.7554/elife.105576.3
Primary Topic
Metabolomics and Mass Spectrometry Studies
Type
article
Field-Weighted Citation Impact
0.00

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article

Pyruvate and related energetic metabolites modulate resilience against high genetic risk for glaucoma

Christa Montgomery, Louis R. Pasquale, Jae H. Kang, Yoshihiko Raita et al.
eLife
Metabolomics and Mass Spectrometry Studies
article

Pyruvate and related energetic metabolites modulate resilience against high genetic risk for glaucoma

Christa Montgomery, Louis R. Pasquale, Jae H. Kang, Yoshihiko Raita, Pirro G. Hysi, Keva Li, Ayellet V. Segrè, Simon W. M. John, Kelsey V. Stuart, Nazlee Zebardast, Akiko Hanyuda, Anthony P. Khawaja, Oana A. Zeleznik, Neeru A. Vallabh, Kuang Hu, Nicholas Tolman, Ron Do, Janey L. Wiggs, Chi Zhang
article en

Abstract

A glaucoma polygenic risk score (PRS) can 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 of 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 marginal prediction improvement in PRS-only-based models (p=0.004). We identified a metabolomic signature associated with resilience in the top glaucoma 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 (P interaction = 0.011). Higher total resilience metabolite levels within the highest PRS quartile corresponded to lower glaucoma prevalence (Odds Ratio highest vs. lowest total resilience metabolite quartile =0.71, 95% Confidence Interval = 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 Lmx1b V265D mice. These findings highlight the protective role of pyruvate-related metabolism against glaucoma and suggest potential avenues for therapeutic intervention.

eLifeVol. 14
Broad Institute (US), Brigham and Women's Hospital (US), Massachusetts Eye and Ear Infirmary (US), St Thomas' Hospital (GB), Moorfields Eye Hospital NHS Foundation Trust (GB), Harvard University (US), University of Liverpool (GB), King's College London (GB), Keio University (JP), Aintree University Hospitals NHS Foundation Trust (GB), Brain (Germany) (DE), Okinawa Prefectural Chubu Hospital (JP), Prevention Group (US), Institute of Ophthalmology (MX), Royal College of Physicians (GB), University College London (GB), Columbia University (US), Icahn School of Medicine at Mount Sinai (US)
Columbia University, National Eye Institute, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases
Openalex Percentile: Top 92%
Metabolomics and Mass Spectrometry Studies
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