TY - JOUR T1 - Temporal relationship between hepatitis B virus enhancer II/basal core promoter sequence variation and risk of hepatocellular carcinoma JF - Gut JO - Gut SP - 91 LP - 97 DO - 10.1136/gut.2006.114066 VL - 57 IS - 1 AU - Y-C Chou AU - M-W Yu AU - C-F Wu AU - S-Y Yang AU - C-L Lin AU - C-J Liu AU - W-L Shih AU - P-J Chen AU - Y-F Liaw AU - C-J Chen Y1 - 2008/01/01 UR - http://gut.bmj.com/content/57/1/91.abstract N2 - Background and aims: 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. ER -