Research Papers: Pathology:
Interferon-stimulated gene 15 in hepatitis B-related liver diseases
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Nghiem Xuan Hoan1,2,3,*, Hoang Van Tong1,3,*, Dao Phuong Giang1,2,3,*, Nguyen Linh Toan3,4, Christian G. Meyer1,3, C.-Thomas Bock5, Peter G. Kremsner1,3, Le Huu Song2,3,** and Thirumalaisamy P. Velavan1,3,4,**
1 Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany
2 108 Military Central Hospital, Hanoi, Vietnam
3 Vietnamese-German Center for Medical Research, Hanoi, Vietnam
4 Department of Pathophysiology, Vietnam Military Medical University, Hanoi, Vietnam
5 Department of Infectious Diseases, Robert Koch Institute, Berlin, Germany
* These authors have contributed equally to this work
** Shared senior authors
Thirumalaisamy P. Velavan, email:
Keywords: HBV infection, liver diseases, ISG15, ISG15 polymorphism, ISGlation, Pathology Section
Received: June 11, 2016 Accepted: September 05, 2016 Published: September 10, 2016
This study investigates the association of Interferon-stimulated gene 15 (ISG15) polymorphisms, ISG15 serum levels and expression with HBV-related liver diseases. The ISG15 promoter and the two exons of the gene were screened for polymorphisms in 766 HBV-infected patients and in 223 controls. Soluble ISG15 levels were measured by ELISA. ISG15 mRNA expression was quantified by qRT-PCR in 36 tumor and adjacent non-tumor tissues. The exon 2 allele rs1921A was found associated with decreased progression of HBV-related liver diseases (LC vs. CHB: OR = 0.6, 95%CI = 0.4-0.8, adjusted P = 0.003; HCC vs. CHB: OR = 0.6, 95%CI = 0.4-0.9, adjusted P = 0.005). The rs1921AA genotype was associated with low levels of AST, ALT and total bilirubin, but with high prothrombin levels (P < 0.05). ISG15 serum levels were higher among HBV patients compared to controls (P < 0.0001) and positively associated with HBV-related liver diseases, with highest levels among LC patients. ISG15 levels were correlated with HBV-DNA loads (P = 0.001). In non-tumor tissues from HCC patients, ISG15 mRNA expression was increased in HBV compared to non-HBV infection (P = 0.016). The ISG15 rs1921 variant and ISG15 expression are associated with HBV-related liver diseases. Taken together, ISG15 appears to be a proviral factor involved in HBV replication and triggering progression of HBV-related liver diseases.
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