Patients With Specific Types of Lipids May Be at Higher Risk of Developing Blinding Eye Disease

Principal Investigator: Louis R. Pasquale, MD, FARVO, Deputy Chair for Ophthalmology Research for the Mount Sinai Health System

Co-First Authors: Oana A. Zeleznik, PhD, Instructor in Medicine at Brigham and Women’s Hospital and Jae H. Kang, ScD, Assistant Professor of Medicine at Brigham and Women’s Hospital, a founding member of the Mass General Brigham Healthcare System

Journal: Nature Communications – May Issue

https://www.nature.com/articles/s41467-023-38466-w

Bottom Line:  Lipid metabolism is dysregulated in and associated with primary open-angle glaucoma (POAG), particularly for the subtype of the disease associated with early central visual loss. More lipoprotein analysis needs to be done in glaucoma to determine the source.

Why the Study Is Unique: This is the largest glaucoma metabolomics study performed 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, the dysregulation of lipid metabolism may suggest new therapies for this type of glaucoma.

What the Study Found: Higher levels of two lipids—diglycerides (DGs) and triglycerides (TGs)—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 “Health Professionals’ Follow-Up Study,” beginning in 1989, and stored them at ultra-low temperatures. Researchers followed participants and confirmed which ones developed POAG. They selected matched controls accounting for age, sex, and other factors. They only chose cases with blood on file before a glaucoma diagnosis. Researchers performed metabolic profiling of these samples with extensive quality controls using an exhaustive statistical analysis. They confidently reported 369 metabolites linked to glaucoma cases.

Researchers replicated these findings using the UK Biobank where more than 100,000 participants had metabolomics data and over 2,000 had glaucoma based on self-reporting or hospital-based coding data. The sample collection and establishment of glaucoma diagnosis took place between 2006 and 2010. Researchers analyzed samples and reported data back to the UK BioBank in 2019. They retrieved results through a research application.

The Findings: Five individual lipids out of 369 metabolites from 39 different classes demonstrated a nominal adverse association with POAG in health professionals after adjusting for many risk factors including race, ethnicity, family history of glaucoma, smoking status, and physical activity. Researchers then evaluated metabolite classes in relation to POAG. They found that DGs and TGs collectively were adversely associated with POAG. POAG is stratified into cases with paracentral vision loss and those with peripheral vision loss. Even though there were fewer cases of paracentral vision loss in this study, the adverse reactions for DGs/TGs were stronger in glaucoma patients with paracentral vision loss when compared to those with peripheral vision loss. The adverse relationship between TGs, DGs and glaucoma was replicated in the UK Biobank.

What These Findings Mean: The findings of high TGs and high DGs and glaucoma raise questions about whether statin use could correct dyslipidemia and lower the risk of glaucoma. Observational studies that have evaluated statins in relation to glaucoma have been inconsistent. Additionally, lipid biomarkers may also implicate insulin resistance in glaucoma. Looking at markers that collectively associate with insulin resistance in glaucoma may be useful.

What’s Next for This Work: TGs/DGs in the blood are stored in the core lipoprotein carriers, and researchers plan to explore which of these carriers might contribute to POAG risk. Researchers also plan to perform proteomics studies to understand how lipids are metabolized in glaucoma patients. They will also see whether associations are modified by glaucoma genetic risk scores. The adverse association between selected lipids and glaucoma may be magnified in people with a higher genetic predisposition to glaucoma. Two genes associated with glaucoma—ABCA1 and CAV1/2—are involved with 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

Quotes:  

Louis R. Pasquale, MD, FARVO, Deputy Chair for Ophthalmology Research for the Mount Sinai Health System and Principal Investigator:

“Our data strongly implicate altered lipid metabolism in the etiology of primary open-angle glaucoma, particularly for the subtype with early central vision loss. Blood lipid biomarkers, which investigators have found to be adversely associated with POAG in prevalent cases, were also elevated in the blood of POAG patients before they were diagnosed, suggesting they are upstream markers of the disease.”

Oana A. Zeleznik, PhD, Instructor in Medicine at Brigham and Women’s Hospital and Jae H. Kang, ScD,  Assistant Professor of Medicine at Brigham and Women’s Hospital

 “Our study is the first to assess associations between pre-diagnostic circulating metabolites and POAG risk in two large independent datasets.”

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