Association between Hepatitis B Virus X Gene Mutations and Clinical Status in Patients with Chronic Hepatitis B Infection
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Background/Aims: Few reports have described the association between mutations in the entire X gene of the hepatitis B virus (HBV) and the clinical status of HBV-infected patients. We studied the association between HBV X gene mutations and the disease status of patients infected with HBV genotype C. Methods: Mutations in the HBV X genes of 194 patients were determined by direct sequencing. The subject population consisted of patients with chronic hepatitis (n=60), liver cirrhosis (n=65), and hepatocellular carcinoma (HCC) (n=69). The sequencing results of these 3 groups were compared. Results: Each of the mutations G1386M, C1485T, C1653T, T1753V, A1762T, and G1764A was signifi cantly associated with the patient’s clinical status. The T1753V (p<0.001) and A1762T/G1764A (p<0.001)mutations were found more frequently in Hepatitis B e antigen (HBeAg)-negative than in HBeAg-positive patients. Specifi c X gene mutations (G1386M, C1653T, and A1762T/G1764A) were more prevalent in patients with liver cirrhosis and HCC than in chronic hepatitis patients (p<0.005 for all). In addition, the T1753V (p<0.001) and C1485T (p<0.001)mutations were signifi cantly more prevalent in HCC patients than in chronic hepatitis patients. Only the prevalence of the T1753V mutation increased as the HBV infection progressed from liver cirrhosis to HCC (p=0.023). Conclusions: Our fi ndings show a difference in the pattern of X gene mutations that were associated with the clinical status of patients with chronic HBV infection.
Abstract
Background/Aims: Few reports have described the association between mutations in the entire X gene of the hepatitis B virus (HBV) and the clinical status of HBV-infected patients. We studied the association between HBV X gene mutations and the disease status of patients infected with HBV genotype C. Methods: Mutations in the HBV X genes of 194 patients were determined by direct sequencing. The subject population consisted of patients with chronic hepatitis (n=60), liver cirrhosis (n=65), and hepatocellular carcinoma (HCC) (n=69). The sequencing results of these 3 groups were compared. Results: Each of the mutations G1386M, C1485T, C1653T, T1753V, A1762T, and G1764A was signifi cantly associated with the patient’s clinical status. The T1753V (p<0.001) and A1762T/G1764A (p<0.001)mutations were found more frequently in Hepatitis B e antigen (HBeAg)-negative than in HBeAg-positive patients. Specifi c X gene mutations (G1386M, C1653T, and A1762T/G1764A) were more prevalent in patients with liver cirrhosis and HCC than in chronic hepatitis patients (p<0.005 for all). In addition, the T1753V (p<0.001) and C1485T (p<0.001)mutations were signifi cantly more prevalent in HCC patients than in chronic hepatitis patients. Only the prevalence of the T1753V mutation increased as the HBV infection progressed from liver cirrhosis to HCC (p=0.023). Conclusions: Our fi ndings show a difference in the pattern of X gene mutations that were associated with the clinical status of patients with chronic HBV infection.
참고문헌 (43)
- Lee WM, "Hepatitis B virus infection", N Engl J Med, 337, pp.1733~1745 (1997)
- Ganem D, "The molecular biology of the hepatitis B viruses", Annu Rev Biochem, 56, pp.651~693 (1987)
- Schaller H, "Transcriptional control of hepadnavirus gene expression", Curr Top Microbiol Immunol, 168, pp.21~39 (1991)
- Mayans MV, "Risk factors for hepatocellular carcinoma in Catalonia, Spain", Int J Cancer, 46, pp.378~381 (1990)
- London WT, "Viral, host and environmental risk factors for hepatocellular carcinoma: a prospective study in Haimen City, China", Intervirology, 38, pp.155~161 (1995)
- Omata M, "Mutations in the precore region of hepatitis B virus DNA in patients with fulminant and severe hepatitis", N Engl J Med, 324, pp.1699~1704 (1991)
- Fattovich G, "Long-term follow-up of anti-HBe-positive chronic active hepatitis B", Hepatology, 8, pp.1651~1654 (1988)
- Lindh M, "Hepatitis B virus DNA levels, precore mutations, genotypes and histological activity in chronic hepatitis B", J Viral Hepat, 7, pp.258~267 (2000)
- Thomas HC, "Inducer and suppressor T-cells in hepatitis B virus-induced liver disease.", Hepatology, 2, pp.202~204 (1982)
- Eddleston AL, "Immunopathological mechanisms of liver cell injury in chronic hepatitis B virus infection", J Hepatol, 3(Suppl 2), pp.S17~S23 (1986)
- Omata M, "Correlation of hepatitis B virus DNA and antigens in the liver. A study in chronic liver disease", Gastroenterology, 92, pp.192~196 (1987)
- Tanaka Y, "Specific mutations in enhancer II", core promoter of hepatitis B virus subgenotypes C1, J Hepatol, pp.2006, 45[DOI]
- Kim JK, "Specific Mutations in the Enhancer II", Core Promoter, Journal Of Medical Virology, pp.2009, 81(6)[DOI]
- Chou YC, "Temporal relationship between hepatitis B virus enhancer II", basal core promoter sequence variation and risk of hepatocellular carcinoma, 2008, pp.57, 91~97
- Yuen MF, "Risk for hepatocellular carcinoma with respect to hepatitis B virus genotypes B", C, specific mutations of enhancer II, precore regions and HBV DNA levels, pp.Gut, 2008[DOI]
- Shinkai N, "Influence of hepatitis B virus X and core promoter mutations on hepatocellular carcinoma among patients infected with subgenotype C2", J Clin Microbiol, 45, pp.3191~3197 (2007)
- Gu JM, "HBx modulates iron regulatory protein 1-mediated iron metabolism via reactive oxygen species", VIRUS RESEARCH, 133, pp.167~177, ELSEVIER SCIENCE BV
- Shirakata Y, "Hepatitis B virus X protein induces cell death by causing loss of mitochondrial membrane potential", J Biol Chem, 278, pp.22071~22078 (2003)
- Kim S, "Hepatitis B virus X protein induces perinuclear mitochondrial clustering in microtubule- and Dyneindependent manners", J Virol, 81, pp.1714~1726 (2007)
- Lee MO, "Hepatitis B virus X protein induced expression of interleukin 18 (IL-18): a potential mechanism for liver injury caused by hepatitis B virus (HBV) infection", J Hepatol, 37, pp.380~386 (2002)
- Lara-Pezzi E, "The hepatitis B virus X protein up-regulates tumor necrosis factor alpha gene expression in hepatocytes", Hepatology, 28, pp.1013~1021 (1998)
- Koike K, "Hepatitis B virus X gene is implicated in liver carcinogenesis", Cancer Lett, 286, pp.60~68 (2009)
- Bock CT, "Subcellular mislocalization of mutant hepatitis B X proteins contributes to modulation of STAT", SOCS signaling in hepatocellular carcinoma, 2008, pp.51, 432~443
- Kim HJ, "Hepatitis B virus X mutations occurring naturally associated with clinical severity of liver disease among Korean patients with chronic genotype C infection", J Med Virol, 80, pp.1337~1343 (2008)
- Takahashi K, "Hepatitis B virus genomic sequence in the circulation of hepatocellular carcinoma patients: comparative analysis of 40 full-length isolates", Arch Virol, 143, pp.2313~2326 (1998)
- Sung JJ, "Genotype-specific genomic markers associated with primary hepatomas, based on complete genomic sequencing of hepatitis B virus", J Virol, 82, pp.3604~3611 (2008)
- Thompson JD, "The CLUSTAL_X windows interface: flexible strategies for multiple sequence alignment aided by quality analysis tools", Nucleic Acids Res, 25, pp.4876~4882 (1997)
- Kimura M, "A simple method for estimating evolutionary rates of base substitutions through comparative studies of nucleotide sequences", J Mol Evol, 16, pp.111~120 (1980)
- Dong Q, "A1762T", G1764A mutations of hepatitis B virus, associated with the increased risk of hepatocellular carcinoma, reduce basal core promoter activities, 2008, pp.374, 773~776
- Stemler M, "Mapping of B-cell epitopes of the human hepatitis B virus X protein", J Virol, 64, pp.2802~2809 (1990)
- Muroyama R, "Nucleotide change of codon 38 in the X gene of hepatitis B virus genotype C is associated with an increased risk of hepatocellular carcinoma", J Hepatol, 45, pp.805~812 (2006)
- Choi CS, "X gene mutations in hepatitis B patients with cirrhosis, with and without hepatocellular carcinoma", J Med Virol, 81, pp.1721~1725 (2009)
- Yuh CH, "Transcriptional regulation of precore and pregenomic RNAs of hepatitis B virus", J Virol, 66, pp.4073~4084 (1992)
- López-Cabrera M, "Multiple liverspecific factors bind to the hepatitis B virus core", pregenomic promoter: trans-activation and repression by CCAAT, Proc Natl Acad Sci U S A, pp.1990, 87[DOI]
- Lee H, "Liver-specific enhancer II is the target for the p53-mediated inhibition of hepatitis B viral gene expression", J Biol Chem, 273, pp.19786~19791 (1998)
- Sirma H, "Hepatitis B virus X mutants, present in hepatocellular carcinoma tissue abrogate both the antiproliferative and transactivation effects of HBx", Oncogene, 18, pp.4848~4859 (1998)
- Wang Z, "Clinical and virological characteristics of hepatitis B virus subgenotypes Ba, C1, and C2 in China", J Clin Microbiol, 45, pp.1491~1496 (2007)
- Miyakawa Y, "The molecular basis of hepatitis B e antigen (HBeAg)-negative infections", J Viral Hepat, 4, pp.1~8 (1997)
- Kidd AH, "A revised secondary structure model for the 3’-end of hepatitis B virus pregenomic RNA", Nucleic Acids Res, 24, pp.3295~3301 (1996)
- Jammeh S, "Effect of basal core promoter and pre-core mutations on hepatitis B virus replication", J Gen Virol, 89(Pt 4), pp.901~909 (2008)
- Lin X, "Biological impacts of “hot-spot” mutations of hepatitis B virus X proteins are genotype B and C differentiated", World J Gastroenterol, 11, pp.4703~4708 (2005)
- Liu S, "Associations between hepatitis B virus mutations and the risk of hepatocellular carcinoma: a metaanalysis", J Natl Cancer Inst, 101, pp.1066~1082 (2009)
- Günther S, "Type, prevalence, and significance of core promoter", enhancer II mutations in hepatitis B viruses from immunosuppressed patients with severe liver disease, 1996, pp.70, 8318~8331
