J Korean Med Sci.  2011 Apr;26(4):546-550. 10.3346/jkms.2011.26.4.546.

Precore and Core Promoter Mutations of the Hepatitis B Virus Gene in Chronic Genotype C -Infected Children

• Kang HS
• Kang KS
• Song BC

• KMID: 1777886
• DOI: http://doi.org/10.3346/jkms.2011.26.4.546

Abstract

The precore (G1896A) and core promoter (A1762T, G1764A) mutations of the hepatitis B virus gene are known to be associated with changes in immunologic phase or the progression to complicated liver disease in adults. We analyzed these mutations in chronically HBV-infected children. Serum was collected from 37 children with chronic HBV infection from March 2005 to September 2008. HBV DNA extraction and nested PCR were followed by sequencing of the PCR products. The children were 6.7 +/- 4.6 yr old. All of 37 children had HBV genotype C. Of the cohort, 31 (83.8%) were HBeAg-positive and 6 (16.2%) were HBeAg-negative; the former group comprised 18 (48.6%) who were in the immune-tolerance phase (ITP) and 13 (35.2%) in the immune-clearance phase (ICP). Most of the patients had HBV DNA levels of > 1.0 x 10(8) copies/mL. In the ITP group, only 1 (5.5%) had core promoter mutations, and none had the precore mutation. In the ICP group, only 2 (15.4%) had core promoter mutations; the remaining 6 patients had HBV DNA levels of < 2.0 x 10(3) copies/mL and no core promoter/precore mutations. The very low incidence of the precore/core promoter gene mutation, in children, suggests that these mutations may be the result of life-long chronic HBV infection.

Keyword

Hepatitis B Virus; Mutation; Child

MeSH Terms

Adolescent
Alanine Transaminase/blood
Aspartate Aminotransferases/blood
Child
Child, Preschool
Cohort Studies
DNA, Viral/blood
Female
Genotype
Hepatitis B Core Antigens/*genetics
Hepatitis B virus/*genetics
Hepatitis B, Chronic/immunology/*virology
Humans
Infant
Male
Mutation
Promoter Regions, Genetic
Sequence Analysis, DNA

Reference

1. Yuen MF, Lai CL. Natural history of chronic hepatitis B virus infection. J Gastroenterol Hepatol. 2000. 15:Suppl. E20–E24.

2. Rehermann B, Nascimbeni M. Immunology of hepatitis B virus and hepatitis C virus infection. Nat Rev Immunol. 2005. 5:215–229.

3. Carman WF, Jacyna MR, Hadziyannis S, Karayiannis P, McGarvey MJ, Makris A, Thomas HC. Mutation preventing formation of hepatitis b e antigen in patients with chronic hepatitis b infection. Lancet. 1989. 2:588–591.

4. Song BC, Cui XJ, Kim HU, Cho YK. Sequential accumulation of the basal core promoter and the precore mutations in the progression of hepatitis b virus-related chronic liver disease. Intervirology. 2006. 49:266–273.

5. Chu CJ, Keeffe EB, Han SH, Perrillo RP, Min AD, Soldevila-Pico C, Carey W, Brown RS Jr, Luketic VA, Terrault N, Lok AS. U.S. HBV Epidemiology Study Group. Prevalence of HBV precore/core promoter variants in the United States. Hepatology. 2003. 38:619–628.

6. Chun YK, Kim JY, Woo HJ, Oh SM, Kang I, Ha J, Kim SS. No significant correlation exists between core promoter mutations, viral replication, and liver damage in chronic hepatitis B infection. Hepatology. 2000. 32:1154–1162.

7. Liaw YF, Chu CM. Hepatitis B virus infection. Lancet. 2009. 373:582–592.

8. Naito H, Hayashi S, Abe K. Rapid and specific genotyping system for hepatitis B virus corresponding to six major genotypes by PCR using type-specific primers. J Clin Microbiol. 2001. 39:362–364.

9. Yuh CH, Chang YL, Ting LP. Transcriptional regulation of precore and pregenomic RNAs of hepatitis B virus. J Virol. 1992. 66:4073–4084.

10. Chen IH, Huang CJ, Ting LP. Overlapping initiator and TATA box functions in the basal core promoter of hepatitis B virus. J Virol. 1995. 69:3647–3657.

11. Locarnini S, McMillan J, Bartholomeusz A. The hepatitis B virus and common mutants. Semin Liver Dis. 2003. 23:5–20.

12. Pumpens P, Borisova GP, Crowther RA, Grens E. Hepatitis B virus core particles as epitope carriers. Intervirology. 1995. 38:63–74.

13. Hou J, Lau GK, Cheng J, Cheng CC, Luo K, Carman WF. T1762/a1764 variants of the basal core promoter of hepatitis b virus; serological and clinical correlations in chinese patients. Liver. 1999. 19:411–417.

14. Friedt M, Gerner P, Lausch E, Trübel H, Zabel B, Wirth S. Mutations in the basic core promotor and the precore region of hepatitis B virus and their selection in children with fulminant and chronic hepatitis B. Hepatology. 1999. 29:1252–1258.

15. Chen CH, Lee CM, Lu SN, Changchien CS, Eng HL, Huang CM, Wang JH, Hung CH, Hu TH. Clinical significance of hepatitis B virus (HBV) genotypes and precore and core promoter mutations affecting HBV e antigen expression in Taiwan. J Clin Microbiol. 2005. 43:6000–6006.

16. Lin CL, Liao LY, Wang CS, Chen PJ, Lai MY, Chen DS, Kao JH. Basal core-promoter mutant of hepatitis B virus and progression of liver disease in hepatitis B e antigen-negative chronic hepatitis B. Liver Int. 2005. 25:564–570.

17. Kim HJ, Yoo BC. The prevalence and clinical significance of precore and core promoter mutations in Korean patients with chronic hepatitis B virus infection. Korean J Hepatol. 2002. 8:149–156.

18. Song BC, Cui XJ, Kim H. Hepatitis B virus genotypes in Korea: an endemic area of hepatitis B virus infection. Intervirology. 2005. 48:133–137.

19. Lin CL, Liao LY, Liu CJ, Chen PJ, Lai MY, Kao JH, Chen DS. Hepatitis B genotypes and precore/basal core promoter mutants in HBeAg-negative chronic hepatitis B. J Gastroenterol. 2002. 37:283–287.

20. Funk ML, Rosenberg DM, Lok AS. World-wide epidemiology of HBeAg-negative chronic hepatitis B and associated precore and core promoter variants. J Viral Hepat. 2002. 9:52–61.

21. Wintermeyer P, Gerner P, Gehring S, Karimi A, Wirth S. Prevalence of hepatitis B virus precore stop codon mutations in chronically infected children. World J Gastroenterol. 2006. 12:2235–2238.

22. Ni YH, Chang MH, Hsu HY, Tsuei DJ. Longitudinal study on mutation profiles of core promoter and precore regions of the hepatitis B virus genome in children. Pediatr Res. 2004. 56:396–399.

23. Barbera C, Calvo P, Coscia A, Perugini L, Dastoli G, Randone A, Bonino F, Brunetto MR. Precore mutant hepatitis B virus and outcome of chronic infection and hepatitis in hepatitis B e antigen-positive children. Pediatr Res. 1994. 36:347–350.

24. Chang MH, Hsu HY, Ni YH, Tsai KS, Lee PI, Chen PJ, Hsu YL, Chen DS. Precore stop codon mutant in chronic hepatitis B virus infection in children: its relation to hepatitis B e seroconversion and maternal hepatitis B surface antigen. J Hepatol. 1998. 28:915–922.

25. Lim SG, Cheng Y, Guindon S, Seet BL, Lee LY, Hu P, Wasser S, Peter FJ, Tan T, Goode M, Rodrigo AG. Viral quasi-species evolution during hepatitis Be antigen seroconversion. Gastroenterology. 2007. 133:951–958.

26. Hadziyannis SJ, Vassilopoulos D. Hepatitis B e antigen-negative chronic hepatitis B. Hepatology. 2001. 34:617–624.

27. Söderström A, Norkrans G, Conradi N, Krantz M, Horal P, Lindh M. Histologic activity of childhood chronic hepatitis B related to viremia levels, genotypes, mutations, and epidemiologic factors. J Pediatr Gastroenterol Nutr. 2002. 35:487–494.

28. Odgerel Z, Nho KB, Moon JY, Kee SH, Park KS, Song KJ, Baek LJ, Yeon JE, Byun KS, Lee CH, Song JW. Complete genome sequence and phylogenetic analysis of hepatitis B virus (HBV) isolates from patients with chronic HBV infection in Korea. J Med Virol. 2003. 71:499–503.

29. Yuen MF, Sablon E, Tanaka Y, Kato T, Mizokami M, Doutreloigne J, Yuan HJ, Wong DK, Sum SM, Lai CL. Epidemiological study of hepatitis B virus genotypes, core promoter and precore mutations of chronic hepatitis B infection in Hong Kong. J Hepatol. 2004. 41:119–125.

30. Fung SK, Wong FS, Wong DK, Hussain MT, Lok AS. Hepatitis B virus genotypes, precore and core promoter variants among predominantly Asian patients with chronic HBV infection in a Canadian center. Liver Int. 2006. 26:796–804.