TY - JOUR
T1 - The carnitine shuttle pathway is altered in patients with neovascular age-related macular degeneration
AU - Mitchell, Sabrina L.
AU - Uppal, Karan
AU - Williamson, Samantha M.
AU - Liu, Ken
AU - Goodwin Burgess, L.
AU - Tran, Vilinh
AU - Umfress, Allison C.
AU - Jarrell, Kelli L.
AU - Cooke Bailey, Jessica N.
AU - Agarwal, Anita
AU - Pericak-Vance, Margaret
AU - Haines, Jonathan L.
AU - Scott, William K.
AU - Jones, Dean P.
AU - Brantley, Milam A.
N1 - Funding Information:
Supported by National Institutes of Health (NIH; Bethesda, MD, USA) Grants R01 EY22618 (MAB) and R01 EY012118 (MP-V, JLH, WKS, and AA) and an unrestricted departmental award from Research to Prevent Blindness, and by the Clinical and Translational Science Collaborative of Cleveland, KL2TR000440 from the National Center for Advancing Translational 419 Sciences (NCATS) component of the NIH and NIH roadmap for Medical Research (JNCB).
PY - 2018/10
Y1 - 2018/10
N2 - PURPOSE. To identify metabolites and metabolic pathways altered in neovascular age-related macular degeneration (NVAMD). METHODS. We performed metabolomics analysis using high-resolution C18 liquid chromatography-mass spectrometry on plasma samples from 100 NVAMD patients and 192 controls. Data for mass/charge ratio ranging from 85 to 850 were captured, and metabolic features were extracted using xMSanalyzer. Nested feature selection was used to identify metabolites that discriminated between NVAMD patients and controls. Pathway analysis was performed with Mummichog 2.0. Hierarchical clustering was used to examine the relationship between the discriminating metabolites and NVAMD patients and controls. RESULTS. Of the 10,917 metabolic features analyzed, a set of 159 was identified that distinguished NVAMD patients from controls (area under the curve of 0.83). Of these features, 39 were annotated with confidence and included multiple carnitine metabolites. Pathway analysis revealed that the carnitine shuttle pathway was significantly altered in NVAMD patients (P = 0.0001). Tandem mass spectrometry confirmed the molecular identity of five carnitine shuttle pathway acylcarnitine intermediates that were increased in NVAMD patients. Hierarchical cluster analysis revealed that 51% of the NVAMD patients had similar metabolic profiles, whereas the remaining 49% displayed greater variability in their metabolic profiles. CONCLUSIONS. Multiple long-chain acylcarnitines that are part of the carnitine shuttle pathway were significantly increased in NVAMD patients compared to controls, suggesting that fatty acid metabolism may be involved in NVAMD pathophysiology. Cluster analysis suggested that clinically indistinguishable NVAMD patients can be separated into distinct subgroups based on metabolic profiles.
AB - PURPOSE. To identify metabolites and metabolic pathways altered in neovascular age-related macular degeneration (NVAMD). METHODS. We performed metabolomics analysis using high-resolution C18 liquid chromatography-mass spectrometry on plasma samples from 100 NVAMD patients and 192 controls. Data for mass/charge ratio ranging from 85 to 850 were captured, and metabolic features were extracted using xMSanalyzer. Nested feature selection was used to identify metabolites that discriminated between NVAMD patients and controls. Pathway analysis was performed with Mummichog 2.0. Hierarchical clustering was used to examine the relationship between the discriminating metabolites and NVAMD patients and controls. RESULTS. Of the 10,917 metabolic features analyzed, a set of 159 was identified that distinguished NVAMD patients from controls (area under the curve of 0.83). Of these features, 39 were annotated with confidence and included multiple carnitine metabolites. Pathway analysis revealed that the carnitine shuttle pathway was significantly altered in NVAMD patients (P = 0.0001). Tandem mass spectrometry confirmed the molecular identity of five carnitine shuttle pathway acylcarnitine intermediates that were increased in NVAMD patients. Hierarchical cluster analysis revealed that 51% of the NVAMD patients had similar metabolic profiles, whereas the remaining 49% displayed greater variability in their metabolic profiles. CONCLUSIONS. Multiple long-chain acylcarnitines that are part of the carnitine shuttle pathway were significantly increased in NVAMD patients compared to controls, suggesting that fatty acid metabolism may be involved in NVAMD pathophysiology. Cluster analysis suggested that clinically indistinguishable NVAMD patients can be separated into distinct subgroups based on metabolic profiles.
KW - Age-related macular degeneration
KW - Carnitine shuttle
KW - Long-chain acylcarnitines
KW - Metabolomics
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U2 - 10.1167/iovs.18-25137
DO - 10.1167/iovs.18-25137
M3 - Article
C2 - 30326066
AN - SCOPUS:85055073869
VL - 59
SP - 4978
EP - 4985
JO - Investigative Ophthalmology and Visual Science
JF - Investigative Ophthalmology and Visual Science
SN - 0146-0404
IS - 12
ER -