Metabolomics profiles of patients with Wilson disease reveal a distinct metabolic signature
Wilson disease (WD) is characterized by excessive intracellular copper accumulation in liver and brain due to defective copper biliary excretion. With highly varied phenotypes and a lack of biomarkers for the different clinical manifestations, diagnosis and treatment can be difficult.
The aim of the present study was to analyze serum metabolomics profiles of patients with Wilson disease compared to healthy subjects, with the goal of identifying differentially abundant metabolites as potential biomarkers for this condition.
Hydrophilic interaction liquid chromatography-quadrupole time of flight mass spectrometry was used to evaluate the untargeted serum metabolome of 61 patients with WD (26 hepatic and 25 neurologic subtypes, 10 preclinical) compared to 15 healthy subjects. We conducted analysis of covariance with potential confounders (body mass index, age, sex) as covariates and partial least-squares analysis.
After adjusting for clinical covariates and multiple testing, we identified 99 significantly different metabolites (FDR < 0.05) between WD and healthy subjects. Subtype comparisons also revealed significantly different metabolites compared to healthy subjects: WD hepatic subtype (67), WD neurologic subtype (57), WD hepatic-neurologic combined (77), and preclinical (36). Pathway analysis revealed these metabolites are involved in amino acid metabolism, the tricarboxylic acid cycle, choline metabolism, and oxidative stress.
Patients with WD are characterized by a distinct metabolomics profile providing new insights into WD pathogenesis and identifying new potential diagnostic biomarkers.
KeywordsCopper Metabolomics Biomarkers Phenotype
- HILIC-QTOF MS
Hydrophilic interaction liquid chromatography-quadrupole time of flight mass spectrometry
Partial least-squares regression with linear discriminant analysis
False discovery rate
Hepatic-neurologic manifestations combined
Reactive oxygen species
We would like to acknowledge Triston Mosbacher (Department of Public Health Sciences, Division of Biostatistics, University of California, Davis) for his contribution to the analysis.
All authors took part in the study design and contributed to the final draft of the paper. In addition, VM conceived and designed the study, and wrote the paper. GS analyzed and interpreted the data, and wrote the paper. AC and TL provided the samples for the studies. NS proofread, contributed to the discussion, and assisted with arranging the final draft. KK performed the data analysis. DK managed the human subject samples and database, and contributed to data interpretation. All authors read and approved the final manuscript.
This research was supported by the National Institutes of Health/NIDDK through grant number R01DK104770 (to V.M.).
Compliance with ethical standards
Conflict of interest
Conflict of Interest: The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The authors who participated in this study declared they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.
This study was conducted according to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by the Institutional Review Board at the University of California, Davis.
Written informed consent was obtained from each patient and healthy subject in this study.
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