The signature of HBV-related liver disease in peripheral blood mononuclear cell DNA methylation.
BACKGROUND
Hepatitis B virus (HBV)-related liver disease induces liver damage by hepatic immune and inflammatory response. The association between aberrant peripheral blood mononuclear cell (PBMC) DNA methylation and progression of liver disease and fibrosis remains unclear.


RESULTS
Here we applied Infinium 450 K BeadChip investigating PBMC genome-wide methylation profiling of 48 HBV-related liver disease patients including 24 chronic hepatitis B (CHB), 14 compensated liver cirrhosis (LC), and 10 decompensated liver cirrhosis (DLC). In total, there were 7888 differentially methylated CpG sites (36.06% hypermethylation, 63.94% hypomethylation) correlate with liver disease progression. LC was difficult to be diagnosed, intermediating between CHB and DLC. We used least absolute shrinkage and selection operator (LASSO)-logistic regression method to perform a LC predictive model. The predicted probability (P) of having LC was estimated by the combined model: P = 1/(1 - e-x), where X = 11.52 - 2.82 × (if AST within the normal range - 0.19 × (percent methylation of cg05650055) - 0.21 × (percent methylation of cg17149911 ). Pyrosequencing validation and confusion matrix analysis was used for internal testing, area under receiver operating characteristic curve (AUROC) of model was 0.917 (95% CI, 0.80-0.977). On the fibrosis progress, there were 1705 genes in LC compared with CHB, whose differentially methylated CpG sites loading within the "promoter" regions (including TSS1500, TSS200, 5'UTR, and the 1st exon of genes) subject into the enrichment analysis using Ingenuity Pathway Analysis (IPA). There were 113 enriched immune-related pathways indicated that HBV-related liver fibrosis progression caused epigenetic reprogramming of the immune and inflammatory response.


CONCLUSIONS
These data support idea that development of HBV-related chronic liver disease is linked with robust and broad alteration of methylation in peripheral immune system. CpG methylation sites serve as relevant biomarker candidates to monitor and diagnose LC, providing new insight into the immune mechanisms understanding the progression of HBV-related liver fibrosis and cirrhosis.
['Li|Kang|K|', 'Qin|Ling|L|', 'Jiang|Sanjie|S|', 'Li|Ang|A|', 'Zhang|Chi|C|', 'Liu|Guihai|G|', 'Sun|Jianping|J|', 'Sun|Huanqing|H|', 'Zhao|Yan|Y|', 'Li|Ning|N|', 'Zhang|Yonghong|Y|']
D000328:Adult D016022:Case-Control Studies D018899:CpG Islands D019175:DNA Methylation D018450:Disease Progression D044127:Epigenesis, Genetic D005260:Female D005355:Fibrosis D006515:Hepatitis B virus D019694:Hepatitis B, Chronic D059014:High-Throughput Nucleotide Sequencing D006801:Humans D007963:Leukocytes, Mononuclear D008103:Liver Cirrhosis D008107:Liver Diseases D008297:Male D008875:Middle Aged D011401:Promoter Regions, Genetic D012372:ROC Curve
HBV-related liver disease DNA methylation LC predictive model Fibrosis progression Immune-related pathways