Metabolome-Wide Association Study of Primary Open Angle Glaucoma.

PURPOSE: To determine if primary open-angle glaucoma (POAG) patients can be differentiated from controls based on metabolic characteristics. METHODS: We used ultra-high resolution mass spectrometry with C18 liquid chromatography for metabolomic analysis on frozen plasma samples from 72 POAG patients and 72 controls. Metabolome-wide Spearman correlation was performed to select differentially expressed metabolites (DEM) correlated with POAG. We corrected P values for multiple testing using Benjamini and Hochberg false discovery rate (FDR). Hierarchical cluster analysis (HCA) was used to depict the relationship between participants and DEM. Differentially expressed metabolites were matched to the METLIN metabolomics database; both DEM and metabolites significantly correlating with DEM were analyzed using MetaboAnalyst to identify metabolic pathways altered in POAG. RESULTS: Of the 2440 m/z (mass/charge) features recovered after filtering, 41 differed between POAG cases and controls at FDR = 0.05. Hierarchical cluster analysis revealed these DEM to associate into eight clusters; three of these clusters contained the majority of the DEM and included palmitoylcarnitine, hydroxyergocalciferol, and high-resolution METLIN matches to sphingolipids, other vitamin D-related metabolites, and terpenes. MetaboAnalyst also indicated likely alteration in steroid biosynthesis pathways. CONCLUSIONS: Global ultrahigh resolution metabolomics emphasized the importance of altered lipid metabolism in POAG. The results suggest specific metabolic processes, such as those involving palmitoylcarnitine, sphingolipids, vitamin D-related compounds, and steroid precursors, may contribute to POAG status and merit more detailed study with targeted methods.

Mitochondrial haplogroups are associated with severity of diabetic retinopathy.

PURPOSE: To determine if specific mitochondrial haplogroups associate with nonproliferative diabetic retinopathy (NPDR) and proliferative diabetic retinopathy (PDR). METHODS: Deidentified medical records for Caucasian patients with diabetic retinopathy (DR; 153 NPDR and 138 PDR) were obtained from BioVU, Vanderbilt University's electronic, deidentified DNA databank. An independent cohort of Caucasian patients with DR (44 NPDR and 57 PDR) from the Vanderbilt Eye Institute (VEI) was used for validation. We tested for an association between mitochondrial haplogroups and PDR among patients with DR. RESULTS: In the BioVU cohort, PDR frequency among Caucasian DR patients differed significantly by mitochondrial haplogroup (P = 0.027). Replication in the VEI cohort confirmed this association (P = 0.0064). In the combined cohort, patients from the common haplogroup H were more likely to have PDR (odds ratio [OR] = 2.0 [95% confidence interval (CI) = 1.3-3.0], P = 0.0012), while patients from haplogroup Uk were less likely to have PDR (OR = 0.5 [95% CI = 0.3-0.8], P = 0.0049). In logistic regression analyses, the addition of diabetes duration, hemoglobin A1c (HgbA1c) levels, and hypertension had no effect on the associations of haplogroups H and Uk with PDR. CONCLUSIONS: In this study, DR patients from mitochondrial haplogroup H were more likely to have PDR, while DR patients from haplogroup Uk were less likely to have PDR. The association was independent of the major clinical variables affecting PDR. The mitochondrial haplogroups were as strong a risk factor for PDR as were elevated HgbA1c levels.