Plasma metabolomics of primary open-angle glaucoma in three prospective US cohorts and the UK Biobank

Abstract

Purpose: To better understand the etiologic pathways in glaucoma, we aimed to identify pre-diagnostic plasma metabolites associated with glaucoma risk. Methods: In a case-control study from the Nurses Health Study (NHS), NHSII and Health Professionals Follow-Up Study (HPFS), 599 incident primary open-angle glaucoma (POAG) cases (mean time between blood draw and diagnosis was 10.3 years) were 1:1 matched to 599 controls. Plasma metabolites were measured with LC-MS/MS at the Broad Institute (Cambridge, MA, USA); 367 metabolites from 17 metabolite classes passed quality control analyses. For comparison, in a cross-sectional study in the UK Biobank, 168 NMR metabolites (Nightingale, Finland; version 2020) were measured in serum samples from 2,238 prevalent glaucoma cases and 44,723 controls. Metabolites were probit-score transformed for normality; multiple logistic regression was used to identify metabolites associated with POAG in NHS/NHSII/HPFS and glaucoma in UK Biobank. In NHS/NHSII/HPFS, we also used Metabolite Set Enrichment Analysis to identify metabolite classes associated with POAG. All analyses adjusted for established glaucoma risk factors. False discovery rate (FDR) and number of effective tests (NEF) were used to adjust for multiple comparisons. Results: Nine metabolite classes were associated (FDR<0.05) with POAG in NHS/NHSII/HPFS: triglycerides, diglycerides, two lysophospholipids classes [lysophosphatidylcholines and lysophosphatidylethanolamines], and two phospholipid class [phosphatidylethanolamines and phosphatidylcholines] were positively associated, while cholesteryl esters, carnitines, and organic acids and derivatives were inversely associated with POAG risk; further adjustment for covariates minimally altered the results. These associations were particularly stronger for POAG with paracentral visual field loss. In the UK Biobank, notably, triglycerides and phospholipids (from which lysophospholipids are derived through hydrolysis), were confirmed to be associated (p<0.05) with higher glaucoma risk. Also, in the UK Biobank, the metabolites of tyrosine, glucose, and glutamine were positively associated (NEF<0.2) while 3-hydroxybutyrate, acetate, citrate, pyruvate and lactate (the latter 4 being anionic organic acids) were inversely associated with glaucoma (NEF<0.05). Conclusions: Higher levels of glycerides (diglycerides and triglycerides) and phospholipids were adversely associated with glaucoma in both the NHS/NHSII/HPFS and the UK Biobank, suggesting that they play an important role in glaucoma pathogenesis.

Regulatory role of cholesterol in modulating actin dynamics and cell adhesive interactions in the trabecular meshwork

“…Hyperlipidemia is associated with an increased risk of elevated IOP and glaucoma with poor mechanistic understanding (5,6,73,74). Systemic cholesterol levels are closely related to glaucoma occurrence and IOP elevation (3)(4)(5)(6).…”

Lessons From The Glaucoma Foundation Think Tank 2023: A Patient-Centric Approach to Glaucoma

“…Interestingly, while HDL and LDL have opposing associations in the case of cardiovascular diseases, with higher LDL associated with a higher disease risk, and higher HDL associated with a lower risk, the aforementioned data showed instead that both HDL and LDL were positively associated with IOP, thus suggesting that the pathway mediating the relationship between lipids metabolism and IOP is different compared to the one that mediates cardiovascular risk 28 . Further research investigating metabolite profiles in multiple cohorts including both the UK Biobank and US cohorts confirmed these results, indicating the importance of serum lipids in glaucoma pathophysiology with the potential for future development of drugs targeting lipid metabolism 29 …”

“…One great advantage of the UK Biobank is that it includes detailed eye measurements recorded for over 100,000 participants, including intraocular pressure (IOP) determined with the Ocular Response Analyzer and macula region inner retinal thickness values assessed with OCT. The UK Biobank allowed over the years multiple milestone discoveries in the field of glaucoma, including the role of genetics and behavioral risk factors, 15–32 that have been discussed extensively during the Think Tank and will be summarized in detail later in the manuscript. For example, results from the UK Biobank provided insights on the determinants of IOP, the major known risk factor for glaucoma onset and progression: in a cross-sectional study on 110,573 subjects, systolic BP was found to have the strongest association with IOP (partial R 2 : Goldmann-correlated IOPg: 2.30%; corneal-compensated IOPcc: 2.26%) 15 .…”

Glial metabolic alterations during glaucoma pathogenesis

“…POAG was significantly linked to dysregulated fatty acid elongation and synthesis and the degradation of ketone bodies (40). Other studies have identified an adverse correlation between high levels of diglycerides and triglycerides and glaucoma (41) and the association of high total cholesterol levels and low HDL levels with glaucoma (42). When identifying the lipidomic profile of aqueous humour in open-angle glaucoma (OAG), Cabrerizo et al ( 43) reported a higher level of most diacylglycerophosphocholines and 1-ether, 2-acylglycerophosphocholines, 14 sphingomyelins, and 5 cholesteryl esters in OAG patients compared to controls.…”