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1.
Invest Ophthalmol Vis Sci ; 56(8): 5020-8, 2015 Jul.
Article in English | MEDLINE | ID: mdl-26230767

ABSTRACT

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.


Subject(s)
Eye Proteins/metabolism , Glaucoma, Open-Angle/metabolism , Metabolome/physiology , Metabolomics/methods , Aged , Female , Humans , Male , Mass Spectrometry , Middle Aged
2.
Invest Ophthalmol Vis Sci ; 55(9): 5589-95, 2014 Aug 12.
Article in English | MEDLINE | ID: mdl-25118268

ABSTRACT

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.


Subject(s)
Diabetic Retinopathy/genetics , Haplotypes , Mitochondria/genetics , Adult , Aged , Case-Control Studies , Cohort Studies , Diabetes Mellitus, Type 1/complications , Diabetes Mellitus, Type 2/complications , Diabetic Retinopathy/blood , Female , Genotype , Glycated Hemoglobin/analysis , Humans , Male , Middle Aged , Odds Ratio
3.
Invest Ophthalmol Vis Sci ; 55(8): 5291-7, 2014 Jul 24.
Article in English | MEDLINE | ID: mdl-25061114

ABSTRACT

PURPOSE: To test the hypothesis that primary open-angle glaucoma (POAG) patients have a systemic elevation of transforming growth factor ß1 (TGFß1). METHODS: Plasma was prepared from blood samples drawn from patients of the Vanderbilt Eye Institute during clinic visits. Concentrations of total TGFß1 and thrombospondin-1 (TSP1) in plasma were determined by ELISA. Statistical significance of differences between POAG and control samples was evaluated by Mann-Whitney test. Regression analysis was used to evaluate correlations between plasma TGFß1 and patient age and between plasma TGFß1 and TSP1. RESULTS: Plasma samples were obtained from 148 POAG patients and 150 controls. Concentration of total TGFß1 in the plasma of POAG patients (median = 3.25 ng/mL) was significantly higher (P < 0.0001) than in controls (median = 2.46 ng/mL). Plasma TGFß1 was not correlated with age of patient (P = 0.17). Thrombospondin-1 concentration was also significantly higher (P < 0.0001) in POAG patients (median = 0.774 µg/mL) as compared to controls (median = 0.567 µg/mL). Plasma total TGFß1 and TSP1 concentrations were linearly correlated (P < 0.0001). CONCLUSIONS: Plasma samples from POAG patients display elevated total TGFß1 compared to controls, consistent with elevated systemic TGFß1 in POAG patients.


Subject(s)
Glaucoma, Open-Angle/blood , Transforming Growth Factor beta1/blood , Aged , Case-Control Studies , Enzyme-Linked Immunosorbent Assay , Female , Humans , Male , Middle Aged , Regression Analysis , Thrombospondin 1/blood
4.
PLoS One ; 8(8): e72737, 2013.
Article in English | MEDLINE | ID: mdl-24015273

ABSTRACT

PURPOSE: To determine if plasma metabolic profiles can detect differences between patients with neovascular age-related macular degeneration (NVAMD) and similarly-aged controls. METHODS: Metabolomic analysis using liquid chromatography with Fourier-transform mass spectrometry (LC-FTMS) was performed on plasma samples from 26 NVAMD patients and 19 controls. Data were collected from mass/charge ratio (m/z) 85 to 850 on a Thermo LTQ-FT mass spectrometer, and metabolic features were extracted using an adaptive processing software package. Both non-transformed and log2 transformed data were corrected using Benjamini and Hochberg False Discovery Rate (FDR) to account for multiple testing. Orthogonal Partial Least Squares-Discriminant Analysis was performed to determine metabolic features that distinguished NVAMD patients from controls. Individual m/z features were matched to the Kyoto Encyclopedia of Genes and Genomes database and the Metlin metabolomics database, and metabolic pathways associated with NVAMD were identified using MetScape. RESULTS: Of the 1680 total m/z features detected by LC-FTMS, 94 unique m/z features were significantly different between NVAMD patients and controls using FDR (q = 0.05). A comparison of these features to those found with log2 transformed data (n = 132, q = 0.2) revealed 40 features in common, reaffirming the involvement of certain metabolites. Such metabolites included di- and tripeptides, covalently modified amino acids, bile acids, and vitamin D-related metabolites. Correlation analysis revealed associations among certain significant features, and pathway analysis demonstrated broader changes in tyrosine metabolism, sulfur amino acid metabolism, and amino acids related to urea metabolism. CONCLUSIONS: These data suggest that metabolomic analysis can identify a panel of individual metabolites that differ between NVAMD cases and controls. Pathway analysis can assess the involvement of certain metabolic pathways, such as tyrosine and urea metabolism, and can provide further insight into the pathophysiology of AMD.


Subject(s)
Macular Degeneration/blood , Metabolome , Aged , Aged, 80 and over , Case-Control Studies , Databases, Nucleic Acid , Databases, Protein , Female , Humans , Macular Degeneration/physiopathology , Male , Mass Spectrometry , Middle Aged
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