Aberrant DNA methylation of G-protein-coupled bile acid receptor Gpbar1 predicts prognosis of acute-on-chronic hepatitis B liver failure.

The G-protein-coupled bile acid receptor Gpbar1 (TGR5) has been demonstrated to be able to negatively regulate hepatic inflammatory response. In this study, we aimed to determine the methylation status of TGR5 promoter in patients with acute-on-chronic hepatitis B liver failure (ACHBLF) and its predictive value for prognosis. We enrolled 76 consecutive ACHBLF patients, 80 chronic hepatitis B (CHB) patients and 30 healthy controls (HCs). Methylation status of TGR5 promoter in peripheral mononuclear cell (PBMC) was detected by methylation-specific polymerase chain reaction (MSP). The mRNA level of TGR5 was determined by quantitative real-time polymerase chain reaction (RT-qPCR). We found that the frequency of TGR5 promoter methylation was significantly higher in ACHBLF (35/76, 46.05%) than CHB patients (5/80, 6.25%; χ(2) = 32.38, P < 0.01) and HCs (1/30, 3.33%; χ(2) = 17.50, P < 0.01). TGR5 mRNA level was significantly lower (Z = -9.12, P < 0.01) in participants with aberrant methylation than those without. TGR5 methylation showed a sensitivity of 46.05% (35/76), specificity of 93.75% (75/80), positive predictive value (PPV) of 87.5% (35/40) and negative predictive value (NPV) of 64.66% (75/116) in discriminating ACHBLF from CHB patients. ACHBLF patients with methylated TGR5 showed significantly poor survival than those without (P < 0.01). When used to predict 3-month mortality of ACHBLF, TGR5 methylation [area under the receiver operating characteristic curve (AUC) = 0.75] performed significantly better than model for end-stage liver diseases (MELD) score (AUC = 0.65; P < 0.05). Therefore, our study demonstrated that aberrant TGR5 promoter methylation occurred in ACHBLF and might be a potential prognostic marker for the disease.