Abstract
Background and Aims: The diagnosis of Wilson’s disease (WD) is challenging by clinical or genetic criteria. A typical early pathological change of WD is the increased liver lipid deposition and lowered serum triglyceride (TG). Therefore, the contents of serum lipids may provide evidence for screening of biomarkers for WD. Methods: 34 WD patients, 31 WD relatives, and 65 normal controls were enrolled in this study. Serum lipidomics data was acquired by an ultra-high-performance liquid chromatography high-resolution mass spectrometry system, and the data were analyzed by multivariate statistical methods. Results: Of all 510 identified lipids, there are 297 differential lipids between the WD and controls, 378 differential lipids between the relatives and controls, and 119 differential lipids between the patients and relatives. In WD, the abundances of most saturated TG were increased, whereas other unsaturated lipids decreased, including phosphatidylcholine (PC), sphingomyelin (SM), lysophosphatidylcholine (LPC), ceramide (Cer), and phosphatidylserine (PS). We also found many serum lipid species may be used as biomarkers for WD. The areas under the receiver operating characteristic curve (AUC) of PS (35:0), PS (38:5), and PS (34:0) were 0.919, 0.843, and 0.907. The AUCs of TG (38:0) and CerG1 (d42:2) were 0.948 and 0.915 and the AUCs of LPC (17:0) and LPC (15:0) were 0.980 and 0.960, respectively. The lipid biomarker panel exhibits good diagnostic performance for WD. The correlation networks were built among the different groups and the potential mechanisms of differential lipids were discussed. Interestingly, similar lipid profile of WD is also found in their relatives, which indicated the changes may also related to the mutation of the ATP7B gene. Conclusions: Lipid deregulation is another important hallmark of WD besides the deposition of copper. Our lipidomic results provide new insights into the diagnostic and therapeutic targets of WD.
Highlights
Wilson’s disease (WD) is an autosomal recessive genetic disease, which is due to a mutation of the ATP7B gene that leads to a copper metabolism disorder (Ala et al, 2007; Członkowska et al, 2018)
We aimed to describe the metabolic deregulations of WD and identify the characteristics of lipids for the disease
Our lipidomics profiling identified 512 lipids, of which 510 passed quality control (QC) procedures and were eligible for analysis (Table 1). 89.6% peaks had coefficients of variation (CV) below 10% and the CV value of 98.8% of the lipids was less than 30%, indicating that this experiment had good quantitative accuracy. (Supplementary Figure S1)
Summary
Wilson’s disease (WD) is an autosomal recessive genetic disease, which is due to a mutation of the ATP7B gene that leads to a copper metabolism disorder (Ala et al, 2007; Członkowska et al, 2018). Copper ions are deposited in the liver, brain, cornea, kidneys and bone, which progressively aggravates organ damage (Cumings, 1948; Mounajjed et al, 2013; Bandmann et al, 2015). The most prominent clinical presentations of WD are liver disease and cirrhosis, neurologic symptoms and psychiatric features (Mulligan and Bronstein, 2020). Available treatments include zinc salts and chelators, which allow for sufficient control of symptoms. These drugs do not cure the disease and develop severe side effects (Ranucci et al, 2017). The diagnosis of Wilson’s disease (WD) is challenging by clinical or genetic criteria. A typical early pathological change of WD is the increased liver lipid deposition and lowered serum triglyceride (TG). The contents of serum lipids may provide evidence for screening of biomarkers for WD
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