gms | German Medical Science

Background: Metabolomics, the high-throughput analysis of a wide range of metabolites in body fluids, has great potential to uncover biomarkers and pathways that contribute to disease pathophysiology. Studies into metabolomics in age-related macular degeneration (AMD) are scarce and limited by relatively small sample sizes. We therefore performed the largest metabolomics study in AMD to date, to identify associations of amino acids, glycolysis measures, ketone bodies, inflammation-related metabolites, fatty acids and lipoprotein subclasses with AMD.

Methods: A total of 7,753 samples from five cohorts (EUGENDA, Rotterdam Study, ALIENOR, MARS, CORRBI) were analyzed by NMR-based metabolomics at Nightingale Health to quantify 146 individual and 79 derivative metabolite measurements. Data was quality controlled, followed by cohort-specific logistic regression analysis and random effects meta-analysis to determine the association of each measurement with AMD, adjusting for age, gender, and cohort-specific confounders. The significance threshold was determined to be 0.05 after Benjamini-Hochberg correction (false discovery rate correction, FDR) for multiple testing.

Results: Meta-analysis identified 70 individual and 12 derivative measurements significantly associated with AMD. Increasing levels of extra-large (XL-) and large (L-) HDL subclasses were associated with increased risk for AMD (e.g. phospholipids in XL-HDL OR=1.1, 95% CI=1.06-1.20, pFDR=0.01), while small (S-) and medium (M-) HDL subclasses and all VLDL subclasses were associated with decreased risk of AMD (e.g. cholesterol esters in L-VLDL OR=0.90, 95% CI=0.85-0.96, pFDR=0.01). Six dietary amino acids were associated with decreased risk of AMD (e.g. phenylalanine OR=0.86, 95% CI=0.81-0.91, pFDR=1.69x10-4).

Conclusion: HDL and VLDL lipoprotein subclasses showed strong associations with AMD, underscoring an important role for lipid metabolism in AMD pathogenesis. Interestingly, directions of effect differed among HDL subclasses, indicating that HDL particle size and composition are relevant in AMD. Associations with dietary fatty acids and amino acids highlight the role of nutrition in AMD.