{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T23:50:52Z","timestamp":1791071452590,"version":"4.1.0"},"reference-count":32,"publisher":"BMJ","issue":"1","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Gut"],"published-print":{"date-parts":[[2008,1]]},"abstract":"<jats:sec>\n                    <jats:title>Background and aims:<\/jats:title>\n                    <jats:p>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\u2013control study within a cohort of 4841 male HBV carriers who were recruited during the period 1988\u20131992.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/gut.2006.114066","type":"journal-article","created":{"date-parts":[[2007,5,14]],"date-time":"2007-05-14T20:44:00Z","timestamp":1179175440000},"page":"91-97","source":"Crossref","is-referenced-by-count":88,"title":["Temporal relationship between hepatitis B virus enhancer II\/basal core promoter sequence variation and risk of hepatocellular carcinoma"],"prefix":"10.1136","volume":"57","author":[{"given":"Y-C","family":"Chou","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M-W","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C-F","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S-Y","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C-L","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C-J","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W-L","family":"Shih","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P-J","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Y-F","family":"Liaw","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C-J","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2007,5,14]]},"reference":[{"key":"2025112111011755000_57.1.91.1","doi-asserted-by":"publisher","DOI":"10.1055\/s-2004-832922"},{"key":"2025112111011755000_57.1.91.2","doi-asserted-by":"publisher","DOI":"10.1053\/jhep.2001.27221"},{"key":"2025112111011755000_57.1.91.3","doi-asserted-by":"publisher","DOI":"10.1136\/gut.2003.033324"},{"key":"2025112111011755000_57.1.91.4","doi-asserted-by":"publisher","DOI":"10.1053\/jhep.2001.20532"},{"key":"2025112111011755000_57.1.91.5","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/dji043"},{"key":"2025112111011755000_57.1.91.6","doi-asserted-by":"publisher","DOI":"10.1002\/hep.20956"},{"key":"2025112111011755000_57.1.91.7","doi-asserted-by":"crossref","first-page":"2013","DOI":"10.4049\/jimmunol.160.4.2013","article-title":"The secreted hepatitis B precore antigen can modulate the immune response to the nucleocapsid: a mechanism for persistence.","volume":"160","author":"Milich","year":"1998","journal-title":"J Immunol"},{"key":"2025112111011755000_57.1.91.8","doi-asserted-by":"publisher","DOI":"10.1053\/jhep.2003.50453"},{"key":"2025112111011755000_57.1.91.9","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1007\/BF02253575","article-title":"Hepadnaviral X-protein: review of recent progress.","volume":"3","author":"Yen","year":"1996","journal-title":"J Biomed Sci"},{"key":"2025112111011755000_57.1.91.10","doi-asserted-by":"publisher","DOI":"10.1016\/0166-0934(92)90161-6"},{"key":"2025112111011755000_57.1.91.11","doi-asserted-by":"crossref","first-page":"8318","DOI":"10.1128\/jvi.70.12.8318-8331.1996","article-title":"Type, prevalence and significance of core promoter\/enhancer II mutations in hepatitis B virus from immunosuppressed patients with severe liver disease.","volume":"70","author":"Gunther","year":"1996","journal-title":"J Virol"},{"key":"2025112111011755000_57.1.91.12","doi-asserted-by":"crossref","first-page":"6785","DOI":"10.1128\/JVI.72.8.6785-6795.1998","article-title":"Naturally occurring mutations define a novel function of the hepatitis B virus core promoter in core protein expression.","volume":"72","author":"Baumert","year":"1998","journal-title":"J Virol"},{"key":"2025112111011755000_57.1.91.13","doi-asserted-by":"crossref","first-page":"5845","DOI":"10.1128\/jvi.70.9.5845-5851.1996","article-title":"Effects of a naturally occurring mutation in the hepatitis B virus basal core promoter on precore gene expression and viral replication.","volume":"70","author":"Buckwold","year":"1996","journal-title":"J Virol"},{"key":"2025112111011755000_57.1.91.14","doi-asserted-by":"publisher","DOI":"10.1006\/viro.1996.0655"},{"key":"2025112111011755000_57.1.91.15","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.78.16.8524-8535.2004"},{"key":"2025112111011755000_57.1.91.16","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.80.2.587-595.2006"},{"key":"2025112111011755000_57.1.91.17","doi-asserted-by":"publisher","DOI":"10.1002\/jmv.10167"},{"key":"2025112111011755000_57.1.91.18","doi-asserted-by":"publisher","DOI":"10.1053\/gast.2003.50053"},{"key":"2025112111011755000_57.1.91.19","doi-asserted-by":"publisher","DOI":"10.1002\/hep.510290336"},{"key":"2025112111011755000_57.1.91.20","doi-asserted-by":"publisher","DOI":"10.1093\/bib\/5.2.150"},{"key":"2025112111011755000_57.1.91.21","doi-asserted-by":"publisher","DOI":"10.1093\/aje\/kwg156"},{"key":"2025112111011755000_57.1.91.22","doi-asserted-by":"publisher","DOI":"10.1093\/aje\/152.10.897"},{"key":"2025112111011755000_57.1.91.23","doi-asserted-by":"publisher","DOI":"10.1086\/314688"},{"key":"2025112111011755000_57.1.91.24","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1053\/jhep.2003.50352","article-title":"Prevalence of HBV precore\/core promoter variants in the United States.","volume":"38","author":"Chu","year":"2003","journal-title":"Hepatology"},{"key":"2025112111011755000_57.1.91.25","doi-asserted-by":"publisher","DOI":"10.1053\/jhep.2000.19623"},{"key":"2025112111011755000_57.1.91.26","doi-asserted-by":"publisher","DOI":"10.1002\/hep.510310330"},{"key":"2025112111011755000_57.1.91.27","doi-asserted-by":"publisher","DOI":"10.1002\/hep.510310323"},{"key":"2025112111011755000_57.1.91.28","doi-asserted-by":"crossref","first-page":"1705","DOI":"10.1056\/NEJM199106133242405","article-title":"A hepatitis B virus mutant associated with an epidemic of fulminant hepatitis.","volume":"324","author":"Liang","year":"1991","journal-title":"N Engl J Med"},{"key":"2025112111011755000_57.1.91.29","doi-asserted-by":"publisher","DOI":"10.1016\/0042-6822(91)90799-H"},{"key":"2025112111011755000_57.1.91.30","doi-asserted-by":"crossref","first-page":"1058","DOI":"10.1128\/jvi.71.2.1058-1071.1997","article-title":"Members of the nuclear receptor superfamily regulate transcription from the hepatitis B virus nucleocapsid promoter.","volume":"71","author":"Raney","year":"1997","journal-title":"J Virol"},{"key":"2025112111011755000_57.1.91.31","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2006.07.008"},{"key":"2025112111011755000_57.1.91.32","doi-asserted-by":"publisher","DOI":"10.1001\/jama.295.1.65"}],"container-title":["Gut"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/gut.2006.114066","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T19:01:25Z","timestamp":1763751685000},"score":1,"resource":{"primary":{"URL":"https:\/\/gut.bmj.com\/lookup\/doi\/10.1136\/gut.2006.114066"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2007,5,14]]},"references-count":32,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2007,12,19]]},"published-print":{"date-parts":[[2008,1]]}},"alternative-id":["10.1136\/gut.2006.114066"],"URL":"https:\/\/doi.org\/10.1136\/gut.2006.114066","relation":{},"ISSN":["0017-5749","1468-3288"],"issn-type":[{"value":"0017-5749","type":"print"},{"value":"1468-3288","type":"electronic"}],"subject":[],"published":{"date-parts":[[2007,5,14]]}}}