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Temporal relationship between hepatitis B virus enhancer II/basal core promoter sequence variation and risk of hepatocellular carcinoma
  1. Yi-Chun Chou (r91842008{at}ntu.edu.tw)
  1. Graduate Institute of Epidemiology, College of Public Health, National Taiwan University, Taiwan
    1. Ming-Whei Yu (yumw{at}ntu.edu.tw)
    1. Graduate Institute of Epidemiology, College of Public Health, National Taiwan University, Taiwan
      1. Chih-Feng Wu (r93842011{at}ntu.edu.tw)
      1. Graduate Institute of Epidemiology, College of Public Health, National Taiwan University, Taiwan
        1. Shi-Yi Yang (r93842004{at}ntu.edu.tw)
        1. Graduate Institute of Epidemiology, College of Public Health, National Taiwan University, Taiwan
          1. Chih-Lin Lin
          1. Department of Gastroenterology, Ren-Ai Branch, Taipei City Hospital, Taiwan
            1. Chun-Jen Liu (cjliu{at}ha.mc.ntu.edu.tw)
            1. Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital, Taiwan
              1. Wei-Liang Shih (d92842003{at}ntu.edu.tw)
              1. Graduate Institute of Epidemiology, College of Public Health, National Taiwan University, Taiwan
                1. Pei-Jer Chen
                1. Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital, Taiwan
                  1. Yun-Fan Liaw (liveryfl{at}so-net.net.tw)
                  1. Liver Research Unit, Chang Gung University, Taiwan
                    1. Chien-Jen Chen (cjchen{at}ha.mc.ntu.edu.tw)
                    1. Genomics Research Center, Academia Sinica, Taiwan

                      Abstract

                      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 (6 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 1.14-3.25)) 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.

                      • basal core promoter
                      • enhancer II
                      • hepatitis B virus
                      • hepatocellular carcinoma
                      • precore

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