SOCS3 genetic variants and promoter hypermethylation in patients with chronic hepatitis B
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Nghiem Xuan Hoan1,2,3,*, Hoang Van Tong1,3,4,*, Dao Phuong Giang1,2,3,*, Bui Khac Cuong3,4, Nguyen Linh Toan3,4, Heiner Wedemeyer5, C. Thomas Bock6, Peter G. Kremsner1,3, Le Huu Song2,3,**, Thirumalaisamy P. Velavan1,3,4,7,**
1Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany
2Institute of Clinical Infectious Diseases, 108 Military Central Hospital, Hanoi, Vietnam
3Vietnamese-German Center for Medical Research (VG-CARE), Hanoi, Vietnam
4Department of Pathophysiology, Vietnam Military Medical University, Hanoi, Vietnam
5German Center for Infection Research, Department for Gastroenterology, Hepatology, and Endocrinology, Medical School Hannover, Germany
6Department of Infectious Diseases, Robert Koch Institute, Berlin, Germany
7Faculty of Medicine, Duy Tan University, Da Nang, Vietnam
**Shared senior authorship
Thirumalaisamy P. Velavan, email: firstname.lastname@example.org
Keywords: HBV infection, liver diseases, SOCS3 variants, SOCS3 methylation
Received: November 10, 2016 Accepted: January 11, 2017 Published: February 04, 2017
The clinical manifestations of hepatitis B viral infection (HBV) include chronic hepatitis B (CHB), liver cirrhosis (LC) and hepatocellular carcinoma (HCC). The contribution of negative regulator suppressor of cytokine signaling-3 (SOCS3) promoter variants in HBV disease and SOCS3 hypermethylation in tumor tissues were investigated. The SOCS3 promoter region was screened for polymorphisms in 878 HBV patients and in 272 healthy individuals. SOCS3 promoter methylation was examined by bisulfite sequencing. SOCS3 mRNA expression was quantified in 37 tumor and adjacent non-tumor liver tissue specimens. The minor allele rs12953258A was associated with increased susceptibility to HBV infection (OR=1.3, 95%CI=1.1-1.6, adjusted P=0.03). The minor allele rs111033850C and rs12953258A were observed in increased frequencies in HCC and LC patients compared to CHB patients (HCC: OR=1.7, 95%CI=1.1-2.9, adjusted P=0.046; LC: OR=1.4, 95%CI=1.1-1.9, adjusted P=0.017, respectively). HBV patients with rs111033850CC major genotype had decreased viral load (P=0.034), whereas the rs12953258AA major genotype contributed towards increased viral load (P=0.029). Tumor tissues revealed increased hypermethylation compared to adjacent non-tumor tissues (OR=5.4; 95%CI= 1.9-17.1; P=0.001). Increased SOCS3 expression was observed in HBV infested tumor tissues than non-HBV related tumor tissues (P=0.0048). SOCS3 promoter hypermethylation was associated with relatively low mRNA expression in tumor tissues (P=0.0023). In conclusion, SOCS3 promoter variants are associated with HBV susceptibility and SOCS3 hypermethylation stimulates HCC development.
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