title: Temporal relationship between hepatitis B virus enhancer II/basal core promoter sequence variation and risk of hepatocellular carcinoma.
abstract: OBJECTIVE
  To investigate the temporal relationship between sequence variation in the enhancer II (EnhII), basal core promoter (BCP), and precore regions of hepatitis B virus (HBV) and the risk of hepatocellular carcinoma (HCC), we conducted a nested case-control study within a cohort of 4841 male HBV carriers who were recruited during the period 1988-1992.
  
  
  METHODS
  The HBV DNA sequence was determined in baseline blood samples taken from 132 incident cases and 204 controls. Base exchanges during follow-up in 71 cases were compared with 81 controls with samples taken during a similar length of follow-up.
  
  
  RESULTS
  Nine single nucleotide polymorphisms in the EnhII/BCP regions (six of which were genotype C HBV related) were associated with subsequent risk of HCC. The strength of these associations decreased as the lag time between baseline measurement and diagnosis increased over 3 years. However, an increased disease risk in subjects with BCP double variants (mostly T1762/A1764) or genotype C HBV-related variants was evident 9 years or more before diagnosis. The BCP double variants (odds ratio, 1.92 (95% confidence interval, 1.14 to 3.25)) were statistically significantly associated with HCC risk even after adjusting for alanine aminotransferase levels, antibodies against HBV e antigen, HBV genotype, HBV viral load, and other sequence variants. Longitudinal analysis indicated that the increased HCC risks for at-risk sequence variants were attributable to the persistence of these variants.
  
  
  CONCLUSIONS
  HCC risk is associated with sequence variation in the EnhII/BCP regions of HBV, and persistence of at-risk sequence variants is critical for HCC development.
authors.affiliation: Graduate Institute of Epidemiology, College of Public Health, National Taiwan University, Room 522 No.17, Xuzhou Road Zhongzheng District, Taipei City 10055, Taiwan.
authors.forename: Y-C
authors.initials: YC
authors.lastname: Chou
authors.forename: M-W
authors.initials: MW
authors.lastname: Yu
authors.forename: C-F
authors.initials: CF
authors.lastname: Wu
authors.forename: S-Y
authors.initials: SY
authors.lastname: Yang
authors.forename: C-L
authors.initials: CL
authors.lastname: Lin
authors.forename: C-J
authors.initials: CJ
authors.lastname: Liu
authors.forename: W-L
authors.initials: WL
authors.lastname: Shih
authors.forename: P-J
authors.initials: PJ
authors.lastname: Chen
authors.forename: Y-F
authors.initials: YF
authors.lastname: Liaw
authors.forename: C-J
authors.initials: CJ
authors.lastname: Chen
mesh_terms: D000328:Adult; D006528:Carcinoma, Hepatocellular / Q000821:virology*; D016022:Case-Control Studies; D015331:Cohort Studies; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D006515:Hepatitis B virus / Q000235:genetics*; D019694:Hepatitis B, Chronic / Q000821:virology*; D006801:Humans; D008113:Liver Neoplasms / Q000821:virology*; D008297:Male; D008875:Middle Aged; D011401:Promoter Regions, Genetic / Q000235:genetics; D012307:Risk Factors