Plasma Metabolite Profile for Primary Open Angle Glaucoma in Three US Cohorts and the UK Biobank Summary Glaucoma is a progressive optic neuropathy and a leading cause of irreversible blindness worldwide. Primary open-angle glaucoma is the most common form and, however, the etiology of this multifactorial disease is poorly understood. Our objective was to identify plasma metabolites associated with the risk of developing POAG in a case-control study (599 cases and 599 matched controls) nested within the Nurses’ Health Studies and the Health Professionals Follow-up Study. Plasma metabolites were measured with LC-MS/MS at the Broad Institute (Cambridge, MA, USA); 369 metabolites from 18 metabolite classes passed quality control analyses. For comparison, in a cross-sectional study in the UK Biobank, 168 metabolites were measured in plasma samples from 2,238 prevalent glaucoma cases and 44,723 controls using NMR spectroscopy (Nightingale, Finland; version 2020). Here we show higher levels of diglycerides and triglycerides negatively associated with glaucoma in all four cohorts, suggesting that they play an important role in glaucoma pathogenesis. Conclusion : Lipid metabolism is dysregulated and associated with primary open-angle glaucoma (POAG), particularly for the disease subtype associated with early central visual loss. Further analysis of lipoproteins in glaucoma is necessary to determine the source. |
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Patients with specific types of lipids may be at increased risk of developing an eye disease that causes blindness
Why the study is unique : This is the largest glaucoma metabolomics study conducted to date.
Why the study is important : POAG, the most common type of glaucoma, is poorly understood, and the emergence of preclinical lipid biomarkers associated with this condition advances the understanding of this blinding eye disease. More specifically, dysregulation of lipid metabolism may suggest new therapies for this type of glaucoma.
What the study found : Higher levels of two lipids, diglycerides (DG) and triglycerides (TG), were associated with an increased risk of glaucoma in four different study groups.
How the study was conducted : Researchers collected blood samples from health professionals in the "Nurses’ Health Studies" and the "Health Professionals Follow-up Study," starting in 1989, and stored them at ultra-low temperatures . The researchers followed the participants and confirmed which ones developed POAG. They selected matched controls taking into account age, sex and other factors. They only chose cases with blood on file before a glaucoma diagnosis. The researchers performed metabolic profiles of these samples with extensive quality controls using extensive statistical analysis. They confidently reported 369 metabolites related to glaucoma cases.
The researchers replicated these findings using the UK Biobank, where more than 100,000 participants had metabolomics data and more than 2,000 had glaucoma based on hospital coding data or self-reports. Sample collection and establishment of the glaucoma diagnosis took place between 2006 and 2010. The researchers analyzed the samples and reported the data to the UK BioBank in 2019. They obtained the results through a research application.
The results : Five individual lipids from 369 metabolites from 39 different classes demonstrated a nominal adverse association with POAG in healthcare professionals after adjusting for many risk factors, such as race, ethnicity, family history of glaucoma, smoking, and physical activity. The researchers then evaluated the metabolite classes in relation to POAG.
They found that DG and TG together were negatively associated with POAG. POAG is stratified into cases with paracentral vision loss and those with peripheral vision loss. Although there were fewer cases of paracentral vision loss in this study, adverse reactions for DG/TG were stronger in glaucoma patients with paracentral vision loss compared to those with peripheral vision loss. The adverse relationship between TG, DG and glaucoma was replicated in the UK Biobank.
What these findings mean : The findings of high TG and high DG and glaucoma raise questions about whether statin use could correct dyslipidemia and reduce the risk of glaucoma. Observational studies that have evaluated statins in relation to glaucoma have been inconsistent. Furthermore, lipid biomarkers may also implicate insulin resistance in glaucoma. It may be useful to look at the markers that are collectively associated with insulin resistance in glaucoma.
What’s next for this work : TG/DG in the blood is stored in core lipoprotein transporters, and the researchers plan to explore which of these transporters might contribute to POAG risk. The researchers also plan to conduct proteomics studies to understand how lipids are metabolized in glaucoma patients.
They will also see if the associations are modified by glaucoma genetic risk scores. The adverse association between selected lipids and glaucoma may be magnified in people with a greater genetic predisposition to glaucoma. Two genes associated with glaucoma, ABCA1 and CAV1/2, are involved in lipid metabolism and could serve as potential mediators.
Funding : This work was supported by grants from the National Institutes of Health: R01 EY015473 (LRP), NCI UM1 CA186107, U01 CA167552, U01 CA176726, R01 CA49449, R01 CA67262
Principal investigator: Louis R. Pasquale, MD, FARVO, vice president of ophthalmology research at Mount Sinai Health System. Co-first authors: Oana A. Zeleznik, PhD, instructor of medicine at Brigham and Women’s Hospital and Jae H. Kang, ScD, assistant professor of medicine at Brigham and Women’s Hospital, founding member of the Mass General Brigham Healthcare System
Magazine: Nature Communications - May 2023 Edition
