Hypermethylation of the N-Myc Downstream-Regulated Gene 2 Promoter in Peripheral Blood Mononuclear Cells is Associated with Liver Fibrosis in Chronic Hepatitis B

Hypermethylation of the N-Myc Downstream-Regulated Gene 2 Promoter in Peripheral Blood Mononuclear Cells is Associated with Liver Fibrosis in Chronic Hepatitis B

XIN-YUAN LIU,¹ YU-CHEN FAN,^1,2 SHUAI GAO,¹ JING ZHAO,¹ FENG LI,¹ JUN ZHANG¹ and KAI WANG^1,2

¹Department of Hepatology, Qilu Hospital of Shandong University, Jinan, Shandong, China
²Institute of Hepatology, Shandong University, Jinan, Shandong, China

DNA methylation is a fundamental epigenetic modification to regulate gene expression. N-Myc downstream-regulated gene (NDRG) 2 is a cytoplasmic protein and participates in the pathogenesis of liver fibrosis. In this study, the mRNA expression and methylation status of NDRG2 was evaluated in patients with chronic hepatitis B (CHB). The study included 143 CHB patients and 65 normal controls (NC). The mRNA expression of NDRG2 in peripheral blood mononuclear cells (PBMCs) was detected by quantitative real-time polymerase chain reaction. The methylation status of the NDRG2 promoter in PBMCs was detected by methylation-specific polymerase chain reaction. The NDRG2 mRNA level was lower in the CHB group than in the NC group (p < 0.001). Methylation frequency of the NDRG2 promoter was significantly higher in CHB patients than in the NC group (52.44% vs. 26.15%, p < 0.001). Importantly, the relative expression levels of NDRG2 mRNA were significantly lower in the methylated group than in the unmethylated group in both CHB patients and NC (p < 0.001). Furthermore, a lower mRNA level and hypermethylation of NDRG2 were associated with liver fibrosis and inflammation grade in CHB. The aspartate aminotransferase-to-platelet ratio index (APRI) score is widely used to predict liver fibrosis. The mRNA expression levels and methylation status of NDRG2 showed a better score compared to APRI for discriminating the severity of liver fibrosis. In conclusion, hypermethylation of NDRG2 in PBMCs was correlated with decreased mRNA expression and with liver fibrosis. The methylation status of the NDRG2 promoter in PBMCs is a potential noninvasive biomarker to predict the severity of liver fibrosis.

keywords —— chronic hepatitis B; inflammation; liver fibrosis; methylation; NDRG2

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Tohoku J. Exp. Med., 2017, 241, 155-163

Correspondence: Kai Wang, MD, Ph.D., Department of Hepatology, Qilu Hospital of Shandong University and Institute of Hepatology, Shandong University, Wenhuaxi Road 107#, Jinan, Shandong 250012, China.

e-mail: wangdoc876@126.com