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Targeted Metabolomic Analysis in Patients with Wilson Disease Reveals Dysregulated Choline, Methionine and Aromatic Amino Acid Metabolism: Implications for Hepatic and Neurological Phenotypes

ABSTRACT: This study is comparing the plasma metabolomics profile of patients with the genetic disorder, Wilson disease, compared to healthy subjects matched by age, sex, and BMI. Wilson disease (WD) is a genetic copper overload condition characterized by hepatic and neuropsychiatric symptoms with a pathogenesis not well-understood. Choline is essential for lipid metabolism and the methionine cycle; a dysregulated methionine cycle is reported in animal models of WD, though not verified in humans. Defects in neurotransmitters, acetylcholine, and biogenic amines are reported in WD patients with neurological presentations. Precursors of these neuromodulators include choline, phenylalanine, tyrosine, and histidine. Less is known about the circulating levels of these precursors in WD. We aimed to study choline, methionine, aromatic amino acids, and phospholipids in serum profiles of WD subjects compared to healthy subjects (HC).

ORGANISM(S): Human Homo Sapiens

TISSUE(S): Blood

DISEASE(S): Wilson Disease

SUBMITTER: Valentina Medici

PROVIDER: ST001259 | MetabolomicsWorkbench | Tue Oct 01 00:00:00 BST 2019

REPOSITORIES: MetabolomicsWorkbench

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Project description:Wilson disease (WD) is an autosomal recessive disease caused by mutations in ATP7B encoding a copper transporter. Consequent copper accumulation results in a variable WD clinical phenotype involving hepatic, neurologic, and psychiatric symptoms, without clear genotype-phenotype correlations. The goal of this study was to analyze alterations in DNA methylation at the whole-genome level in liver and blood from patients with WD to investigate epigenomic alterations associated with WD diagnosis and phenotype. We used whole-genome bisulfite sequencing (WGBS) to examine distinct cohorts of WD subjects to determine whether DNA methylation could differentiate patients from healthy subjects and subjects with other liver diseases and distinguish between different WD phenotypes. WGBS analyses in liver identified 969 hypermethylated and 871 hypomethylated differentially methylated regions (DMRs) specifically identifying patients with WD, including 18 regions with genome-wide significance. WD-specific liver DMRs were associated with genes enriched for functions in folate and lipid metabolism and acute inflammatory response and could differentiate early from advanced fibrosis in WD patients. Functional annotation revealed that WD-hypermethylated liver DMRs were enriched in liver-specific enhancers, flanking active liver promoters, and binding sites of liver developmental transcription factors, including Hepatocyte Nuclear Factor 4 alpha (HNF4A), Retinoid X Receptor alpha (RXRA), Forkhead Box A1 (FOXA1), and FOXA2. DMRs associated with WD progression were also identified, including 15 with genome-wide significance. However, WD DMRs in liver were not related to large-scale changes in proportions of liver cell types. DMRs detected in blood differentiated WD patients from healthy and disease control subjects, and distinguished between patients with hepatic and neurologic WD manifestations. WD phenotype DMRs corresponded to genes enriched for functions in mental deterioration, abnormal B cell physiology, and as members of the polycomb repressive complex 1 (PRC1). 44 DMRs associated with WD phenotype tested in a small validation cohort had a predictive value of 0.9. We identified a disease-mechanism relevant epigenomic signature of WD that reveals new insights into potential biomarkers and treatments for this complex monogenic disease.

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Targeted Metabolomic Analysis in Patients with Wilson Disease Reveals Dysregulated Choline, Methionine and Aromatic Amino Acid Metabolism: Implications for Hepatic and Neurological Phenotypes

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