Human Plasma Metabolomics in Age-Related Macular Degeneration: Meta-Analysis of Two Cohorts

Abstract

The pathogenesis of age-related macular degeneration (AMD), a leading cause of blindness worldwide, remains only partially understood. This has led to the current lack of accessible and reliable biofluid biomarkers for diagnosis and prognosis, and absence of treatments for dry AMD. This study aimed to assess the plasma metabolomic profiles of AMD and its severity stages with the ultimate goal of contributing to addressing these needs. We recruited two cohorts: Boston, United States (n = 196) and Coimbra, Portugal (n = 295). Fasting blood samples were analyzed using ultra-high performance liquid chromatography mass spectrometry. For each cohort, we compared plasma metabolites of AMD patients versus controls (logistic regression), and across disease stages (permutation-based cumulative logistic regression considering both eyes). Meta-analyses were then used to combine results from the two cohorts. Our results revealed that 28 metabolites differed significantly between AMD patients versus controls (false discovery rate (FDR) q-value: 4.1 × 10−2–1.8 × 10−5), and 67 across disease stages (FDR q-value: 4.5 × 10−2–1.7 × 10−4). Pathway analysis showed significant enrichment of glycerophospholipid, purine, taurine and hypotaurine, and nitrogen metabolism (p-value ≤ 0.04). In conclusion, our findings support that AMD patients present distinct plasma metabolomic profiles, which vary with disease severity. This work contributes to the understanding of AMD pathophysiology, and can be the basis of future biomarkers and precision medicine for this blinding condition.

Metabolomics in Age-Related Macular Degeneration: A Systematic Review

“…Li et al 4 investigated the difference between polypoidal choroidal vasculopathy (PCV) disease and controls, and identified 41 different substances. Laíns et al [25][26][27] conducted three metabolomics studies on the same cohort in the year 2017 to 2019 using plasma and urine samples separately. The results showed that AMD patients and controls had different plasma metabolomics characteristics, 25,27 and the severity stages of AMD can be graded by NMR.…”

A Plasma Metabolomic Profiling of Exudative Age-Related Macular Degeneration Showing Carnosine and Mitochondrial Deficiencies

“…Eight phosphatidylcholines and one lysophosphatidylcholine show significant modifications of their concentrations according to the p-value but without reaching the q-value significance. Modifications of glycerophospholipids have already been reported in the blood of AMD patients [11,12]. Phosphatidylcholines are the main components of circulating lipoproteins that are known to be impaired in AMD [25], thus highlighting their pathophysiological involvement in the disease.…”

“…Eighty-seven discriminant metabolites were identified, most of them belonging to lipid pathways, such as acylcarnitines, triacylglycerols and phosphatidylcholines. Further study of the Coimbra and Boston cohorts by mass spectrometry identified 28 metabolites, differing significantly between the patients and the controls, and 67 metabolites differing with the stage of the disease [11]. These discriminant metabolites were mainly related to nucleoside, amino acid, nitric oxide, energetic and phospholipid metabolism.…”

Metabolomic analysis in ophthalmology

“…Metabolomic profiling provides a practical approach to personalized ophthalmology and has great potential for biomarker discovery for various eye diseases including glaucoma [22][23][24] , age-related macular degeneration 25,26 , diabetic retinopathy 27 , keratoconus 28 , retinal detachment 29 , uveitis 30 , dry eye 31 , and other ocular diseases. Tear fluid 28,32 , aqueous and vitreous humor [33][34][35] , cornea 36 , conjunctiva 37 , and lens 38 samples can be used for metabolomic analysis.…”