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 investigat...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2025-04-01
|
| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/105576 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850179017867526144 |
|---|---|
| author | Keva Li Nicholas Tolman Ayellet V Segrè Kelsey V Stuart Oana A Zeleznik Neeru A Vallabh Kuang Hu Nazlee Zebardast Akiko Hanyuda Yoshihiko Raita Christa Montgomery Chi Zhang Pirro G Hysi Ron Do Anthony P Khawaja Janey L Wiggs Jae H Kang Simon WM John Louis R Pasquale UK Biobank Eye and Vision Consortium |
| author_facet | Keva Li Nicholas Tolman Ayellet V Segrè Kelsey V Stuart Oana A Zeleznik Neeru A Vallabh Kuang Hu Nazlee Zebardast Akiko Hanyuda Yoshihiko Raita Christa Montgomery Chi Zhang Pirro G Hysi Ron Do Anthony P Khawaja Janey L Wiggs Jae H Kang Simon WM John Louis R Pasquale UK Biobank Eye and Vision Consortium |
| author_sort | Keva Li |
| collection | DOAJ |
| description | 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 (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 = 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. |
| format | Article |
| id | doaj-art-c51fc0e6bc6e4d12b5a301a9a373eac1 |
| institution | OA Journals |
| issn | 2050-084X |
| language | English |
| publishDate | 2025-04-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj-art-c51fc0e6bc6e4d12b5a301a9a373eac12025-08-20T02:18:35ZengeLife Sciences Publications LtdeLife2050-084X2025-04-011410.7554/eLife.105576Pyruvate and related energetic metabolites modulate resilience against high genetic risk for glaucomaKeva Li0https://orcid.org/0000-0001-5922-4955Nicholas Tolman1Ayellet V Segrè2Kelsey V Stuart3Oana A Zeleznik4Neeru A Vallabh5Kuang Hu6Nazlee Zebardast7Akiko Hanyuda8Yoshihiko Raita9Christa Montgomery10https://orcid.org/0009-0004-2430-2772Chi Zhang11Pirro G Hysi12Ron Do13https://orcid.org/0000-0002-3144-3627Anthony P Khawaja14Janey L Wiggs15Jae H Kang16https://orcid.org/0000-0003-4812-0557Simon WM John17Louis R Pasquale18https://orcid.org/0000-0002-5835-3496UK Biobank Eye and Vision ConsortiumDepartment of Ophthalmology, Icahn School of Medicine at Mount Sinai, New York, United StatesDepartment of Ophthalmology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, United StatesDepartment of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, United States; Broad Institute of MIT and Harvard, Cambridge, United StatesNIHR Biomedical Research Centre, Moorfields Eye Hospital NHS Foundation Trust, and University College London Institute of Ophthalmology, London, United KingdomChanning Division of Network Medicine, Department of Medicine, Harvard Medical School and Brigham and Women's Hospital, Boston, United StatesDepartment of Eye and Vision Science, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, United Kingdom; St. Paul’s Eye Unit, Liverpool University Hospital NHS Foundation Trust, Liverpool, United KingdomNIHR Biomedical Research Centre, Moorfields Eye Hospital NHS Foundation Trust, and University College London Institute of Ophthalmology, London, United KingdomDepartment of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, United StatesDepartment of Ophthalmology, Keio University School of Medicine, Tokyo, Japan; Epidemiology and Prevention Group, Center for Public Health Sciences, National Cancer Center, Tokyo, JapanOkinawa Kenritsu, Chubu Byoin, Uruma, Okinawa, JapanDepartment of Ophthalmology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, United StatesDepartment of Ophthalmology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, United StatesDepartment of Ophthalmology, St Thomas' Hospital, King's College London, London, United Kingdom; Department of Twin Research & Genetic Epidemiology, St Thomas' Hospital, King's College London, London, United KingdomDepartment of Genetics and Genomics Science, Icahn School of Medicine at Mount Sinai, New York, United StatesNIHR Biomedical Research Centre, Moorfields Eye Hospital NHS Foundation Trust, and University College London Institute of Ophthalmology, London, United KingdomDepartment of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, United States; Broad Institute of MIT and Harvard, Cambridge, United StatesChanning Division of Network Medicine, Department of Medicine, Harvard Medical School and Brigham and Women's Hospital, Boston, United StatesDepartment of Ophthalmology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, United States; Zuckerman Mind Brain Behavior Institute, Columbia University, New York, United StatesDepartment of Ophthalmology, Icahn School of Medicine at Mount Sinai, New York, United StatesA 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 (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 = 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.https://elifesciences.org/articles/105576metabolomicsgeneticsglaucomapyruvateglaucoma resiliencetricarboxylic acid cycle |
| spellingShingle | Keva Li Nicholas Tolman Ayellet V Segrè Kelsey V Stuart Oana A Zeleznik Neeru A Vallabh Kuang Hu Nazlee Zebardast Akiko Hanyuda Yoshihiko Raita Christa Montgomery Chi Zhang Pirro G Hysi Ron Do Anthony P Khawaja Janey L Wiggs Jae H Kang Simon WM John Louis R Pasquale UK Biobank Eye and Vision Consortium Pyruvate and related energetic metabolites modulate resilience against high genetic risk for glaucoma eLife metabolomics genetics glaucoma pyruvate glaucoma resilience tricarboxylic acid cycle |
| title | Pyruvate and related energetic metabolites modulate resilience against high genetic risk for glaucoma |
| title_full | Pyruvate and related energetic metabolites modulate resilience against high genetic risk for glaucoma |
| title_fullStr | Pyruvate and related energetic metabolites modulate resilience against high genetic risk for glaucoma |
| title_full_unstemmed | Pyruvate and related energetic metabolites modulate resilience against high genetic risk for glaucoma |
| title_short | Pyruvate and related energetic metabolites modulate resilience against high genetic risk for glaucoma |
| title_sort | pyruvate and related energetic metabolites modulate resilience against high genetic risk for glaucoma |
| topic | metabolomics genetics glaucoma pyruvate glaucoma resilience tricarboxylic acid cycle |
| url | https://elifesciences.org/articles/105576 |
| work_keys_str_mv | AT kevali pyruvateandrelatedenergeticmetabolitesmodulateresilienceagainsthighgeneticriskforglaucoma AT nicholastolman pyruvateandrelatedenergeticmetabolitesmodulateresilienceagainsthighgeneticriskforglaucoma AT ayelletvsegre pyruvateandrelatedenergeticmetabolitesmodulateresilienceagainsthighgeneticriskforglaucoma AT kelseyvstuart pyruvateandrelatedenergeticmetabolitesmodulateresilienceagainsthighgeneticriskforglaucoma AT oanaazeleznik pyruvateandrelatedenergeticmetabolitesmodulateresilienceagainsthighgeneticriskforglaucoma AT neeruavallabh pyruvateandrelatedenergeticmetabolitesmodulateresilienceagainsthighgeneticriskforglaucoma AT kuanghu pyruvateandrelatedenergeticmetabolitesmodulateresilienceagainsthighgeneticriskforglaucoma AT nazleezebardast pyruvateandrelatedenergeticmetabolitesmodulateresilienceagainsthighgeneticriskforglaucoma AT akikohanyuda pyruvateandrelatedenergeticmetabolitesmodulateresilienceagainsthighgeneticriskforglaucoma AT yoshihikoraita pyruvateandrelatedenergeticmetabolitesmodulateresilienceagainsthighgeneticriskforglaucoma AT christamontgomery pyruvateandrelatedenergeticmetabolitesmodulateresilienceagainsthighgeneticriskforglaucoma AT chizhang pyruvateandrelatedenergeticmetabolitesmodulateresilienceagainsthighgeneticriskforglaucoma AT pirroghysi pyruvateandrelatedenergeticmetabolitesmodulateresilienceagainsthighgeneticriskforglaucoma AT rondo pyruvateandrelatedenergeticmetabolitesmodulateresilienceagainsthighgeneticriskforglaucoma AT anthonypkhawaja pyruvateandrelatedenergeticmetabolitesmodulateresilienceagainsthighgeneticriskforglaucoma AT janeylwiggs pyruvateandrelatedenergeticmetabolitesmodulateresilienceagainsthighgeneticriskforglaucoma AT jaehkang pyruvateandrelatedenergeticmetabolitesmodulateresilienceagainsthighgeneticriskforglaucoma AT simonwmjohn pyruvateandrelatedenergeticmetabolitesmodulateresilienceagainsthighgeneticriskforglaucoma AT louisrpasquale pyruvateandrelatedenergeticmetabolitesmodulateresilienceagainsthighgeneticriskforglaucoma AT ukbiobankeyeandvisionconsortium pyruvateandrelatedenergeticmetabolitesmodulateresilienceagainsthighgeneticriskforglaucoma |