Untargeted serum metabolomics reveals novel metabolite associations and disruptions in amino acid and lipid metabolism in Parkinson's disease.

Autor: Paul KC; Department of Neurology, UCLA David Geffen School of Medicine, Los Angeles, CA, USA. kimberlp@ucla.edu., Zhang K; Department of Epidemiology, UCLA Fielding School of Public Health, Los Angeles, CA, USA., Walker DI; Gangarosa Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA, USA., Sinsheimer J; Department of Human Genetics, UCLA David Geffen School of Medicine, Los Angeles, CA, USA.; Department of Biostatistics, UCLA Fielding School of Public Health, Los Angeles, CA, USA., Yu Y; Center for Health Policy Research, UCLA Fielding School of Public Health, Los Angeles, CA, USA., Kusters C; Department of Human Genetics, UCLA David Geffen School of Medicine, Los Angeles, CA, USA., Del Rosario I; Department of Epidemiology, UCLA Fielding School of Public Health, Los Angeles, CA, USA., Folle AD; Department of Epidemiology, UCLA Fielding School of Public Health, Los Angeles, CA, USA., Keener AM; Department of Neurology, UCLA David Geffen School of Medicine, Los Angeles, CA, USA.; Parkinson's Disease Research, Education, and Clinical Center, Greater Los Angeles Veterans Affairs Medical Center, Los Angeles, CA, USA., Bronstein J; Department of Neurology, UCLA David Geffen School of Medicine, Los Angeles, CA, USA., Jones DP; Department of Medicine, School of Medicine, Emory University, Atlanta, GA, USA., Ritz B; Department of Neurology, UCLA David Geffen School of Medicine, Los Angeles, CA, USA.; Department of Epidemiology, UCLA Fielding School of Public Health, Los Angeles, CA, USA.
Jazyk: angličtina
Zdroj: Molecular neurodegeneration [Mol Neurodegener] 2023 Dec 19; Vol. 18 (1), pp. 100. Date of Electronic Publication: 2023 Dec 19.
DOI: 10.1186/s13024-023-00694-5
Abstrakt: Background: Untargeted high-resolution metabolomic profiling provides simultaneous measurement of thousands of metabolites. Metabolic networks based on these data can help uncover disease-related perturbations across interconnected pathways.
Objective: Identify metabolic disturbances associated with Parkinson's disease (PD) in two population-based studies using untargeted metabolomics.
Methods: We performed a metabolome-wide association study (MWAS) of PD using serum-based untargeted metabolomics data derived from liquid chromatography with high-resolution mass spectrometry (LC-HRMS) using two distinct population-based case-control populations. We also combined our results with a previous publication of 34 metabolites linked to PD in a large-scale, untargeted MWAS to assess external validation.
Results: LC-HRMS detected 4,762 metabolites for analysis (HILIC: 2716 metabolites; C18: 2046 metabolites). We identified 296 features associated with PD at FDR<0.05, 134 having a log 2 fold change (FC) beyond ±0.5 (228 beyond ±0.25). Of these, 104 were independently associated with PD in both discovery and replication studies at p<0.05 (170 at p<0.10), while 27 were associated with levodopa-equivalent dose among the PD patients. Intriguingly, among the externally validated features were the microbial-related metabolites, p-cresol glucuronide (FC=2.52, 95% CI=1.67, 3.81, FDR=7.8e-04) and p-cresol sulfate. P-cresol glucuronide was also associated with motor symptoms among patients. Additional externally validated metabolites associated with PD include phenylacetyl-L-glutamine, trigonelline, kynurenine, biliverdin, and pantothenic acid. Novel associations include the anti-inflammatory metabolite itaconate (FC=0.79, 95% CI=0.73, 0.86; FDR=2.17E-06) and cysteine-S-sulfate (FC=1.56, 95% CI=1.39, 1.75; FDR=3.43E-11). Seventeen pathways were enriched, including several related to amino acid and lipid metabolism.
Conclusions: Our results revealed PD-associated metabolites, confirming several previous observations, including for p-cresol glucuronide, and newly implicating interesting metabolites, such as itaconate. Our data also suggests metabolic disturbances in amino acid and lipid metabolism and inflammatory processes in PD.
(© 2023. The Author(s).)
Databáze: MEDLINE
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