Potential Blood DNA Methylation Biomarker Genes for Diagnosis of Liver Fibrosis in Patients With Biopsy-Proven Non-alcoholic Fatty Liver Disease

Abstract

Background and objectiveThis pilot study aimed to identify potential blood DNA methylation (BDM) biomarker genes for the diagnosis of liver fibrosis in non-alcoholic fatty liver disease (NAFLD).MethodsWe included a total of 16 NAFLD patients with significant (SLF, liver fibrosis stage ≥ 2) and 16 patients with non-significant liver fibrosis (NSLF, fibrosis stages 0–1). The association between BDM and liver fibrosis was analyzed. Genes were selected based on a stepwise-filtering with CpG islands containing significant differentially methylated probes.ResultsThe two groups of patients were distinguishable through both t-distributed stochastic neighbor embedding (t-SNE) analysis and unsupervised hierarchical clustering analysis based on their BDM status. BDM levels were significantly higher in the NSLF group than in the SLF group. The methylation levels in the island and shelf regions were also significantly higher in the NSLF group, as well as the methylation levels in the first exon, 3′-untranslated region, body, ExonBnd, non-intergenic region, transcription start site (TSS)1500, and TSS200 regions (all p < 0.05). BDM status was associated with greater histological liver fibrosis, but not with age, sex, or other histological features of NAFLD (p < 0.05). The methylation levels of the hypomethylated CpG island region of CISTR, IFT140, and RGS14 genes were increased in the NSLF group compared to the SLF group (all p < 0.05).ConclusionBDM may stratify NAFLD patients with significant and non-significant liver fibrosis. The CISTR, IFT140, and RGS14 genes are potential novel candidate BDM biomarkers for liver fibrosis and these pilot data suggest further work on BDM biomarkers is warranted.

The Interplay between Endocrine-Disrupting Chemicals and the Epigenome towards Metabolic Dysfunction-Associated Steatotic Liver Disease: A Comprehensive Review

“…They can also cause non-genomic signaling through activating the PI3K/AKT or MAPK/ERK pathways, resulting in the expression of target genes related to inflammatory pathways, IR, and lipid accumulation [ 4 , 34 , 37 ]. Regarding epigenetic alterations, EDCs can regulate gene expression of proteins involved in DNA methylation and histone modifications [ 38 , 44 , 45 ]. In addition, EDC exposure is also linked to miRNA regulation, leading to dysfunction of related pathways, causing liver damage, and disrupting liver homeostasis [ 28 ].…”

“…Nowadays, DNA methylation is the most frequently studied epigenetic regulation resulting from EDCs [ 38 ]. It has been proposed that DNA methylation could stratify medium-to-severe MASLD fibrosis and be used as a valuable non-invasive tool in the future [ 44 , 45 ]. The main proteins that participate in DNA and histone methylation are the histone methyltransferase and the DNA methyltransferase (DNMT) [ 46 ].…”

Insights into the role of nucleotide methylation in metabolic-associated fatty liver disease

“…Nucleotide methylation markers have the potential as therapeutic targets and staging biomarkers. They are expected to identify patients with early and progressive MAFLD by developing noninvasive operational screening techniques, such as blood-derived biomarkers ( 182 ). Because the nucleotide methylation or demethylation state is reversible, a shift from an HFD to a regular diet and weight loss after bariatric surgery can also partially normalize the DNA methylation profile in MAFLD.…”

Epigenetic Regulation in Lean Nonalcoholic Fatty Liver Disease

“…Recent data have shown that blood DNA methylation markers may differentiate NAFLD patients with nonsignificant liver fibrosis from those with significant fibrosis [ 52 ]. Several genes have been identified as potential blood methylation biomarkers for the diagnosis of liver fibrosis in NAFLD, including CISTR, IFT140, and RGS14 [ 52 ].…”