title: Tear metabolite changes in keratoconus.
abstract: While efforts have been made over the years, the exact cause of keratoconus (KC) remains unknown. The aim of this study was to identify alterations in endogenous metabolites in the tears of KC patients compared with age-matched healthy subjects. Three groups were tested: 1) Age-matched controls with no eye disease (N = 15), 2) KC - patients wearing Rigid Gas permeable lenses (N = 16), and 3) KC - No Correction (N = 14). All samples were processed for metabolomics analysis using LC-MS/MS. We identified a total of 296 different metabolites of which >40 were significantly regulated between groups. Glycolysis and gluconeogenesis had significant changes, such as 3-phosphoglycerate and 1,3 diphosphateglycerate. As a result the citric acid cycle (TCA) was also affected with notable changes in Isocitrate, aconitate, malate, and acetylphosphate, up regulated in Group 2 and/or 3. Urea cycle was also affected, especially in Group 3 where ornithine and aspartate were up-regulated by at least 3 fold. The oxidation state was also severely affected. Groups 2 and 3 were under severe oxidative stress causing multiple metabolites to be regulated when compared to Group 1. Group 2 and 3, both showed significant down regulation in GSH-to-GSSG ratio when compared to Group 1. Another indicator of oxidative stress, the ratio of lactate - pyruvate was also affected with Groups 2 and 3 showing at least a 2-fold up regulation. Overall, our data indicate that levels of metabolites related to urea cycle, TCA cycle and oxidative stress are highly altered in KC patients.
authors.affiliation: Ophthalmology, University of Oklahoma - Dean McGee Eye Institute, Oklahoma City, OK, USA. Electronic address: dimitrios-karamichos@ouhsc.edu.
authors.forename: D
authors.initials: D
authors.lastname: Karamichos
authors.affiliation: Schepens Eye Research Institute/Massachusetts Eye and Ear and the Department of Ophthalmology Harvard Medical School, 20 Staniiford Street, Boston, MA, USA. Electronic address: james_zieske@meei.harvard.edu.
authors.forename: J D
authors.initials: JD
authors.lastname: Zieske
authors.affiliation: Department of Ophthalmology, Aarhus University Hospital, Aarhus C, Denmark. Electronic address: henrseje@rm.dk.
authors.forename: H
authors.initials: H
authors.lastname: Sejersen
authors.affiliation: Ophthalmology, University of Oklahoma - Dean McGee Eye Institute, Oklahoma City, OK, USA. Electronic address: Akhee-SarkerNag@ouhsc.edu.
authors.forename: A
authors.initials: A
authors.lastname: Sarker-Nag
authors.affiliation: Division of Signal Transduction/Mass Spectrometry Core, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. Electronic address: jasara@bidmc.harvard.edu.
authors.forename: John M
authors.initials: JM
authors.lastname: Asara
authors.affiliation: Department of Ophthalmology, Aarhus University Hospital, Aarhus C, Denmark. Electronic address: jesper.hjortdal@dadlnet.dk.
authors.forename: J
authors.initials: J
authors.lastname: Hjortdal
mesh_terms: D000328:Adult; D000704:Analysis of Variance; D016022:Case-Control Studies; D005136:Eye Proteins / Q000378:metabolism*; D005260:Female; D006801:Humans; D007640:Keratoconus / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress / Q000502:physiology; D053719:Tandem Mass Spectrometry; D013666:Tears / Q000378:metabolism*; D055815:Young Adult
chemical_list: D005136:Eye Proteins
keywords: Keratoconus; Metabolomics; Oxidative stress; Pentacam; Rigid Gas Permeable lenses