Association between the various mutations in viral core promoter region to different stages of hepatitis B, ranging of asymptomatic carrier state to hepatocellular carcinoma.
OBJECTIVE
The objective of this study was to determine the association of 19 mutations with frequencies ≥ 10% in the core promoter region of hepatitis B virus (HBV) with chronic hepatitis B (CHB), liver cirrhosis, and hepatocellular carcinoma (HCC).


METHODS
Eight hundred forty-six asymptomatic hepatitis B surface antigen carriers (ASCs), 235 CHB patients, 188 cirrhosis patients, and 190 HCC patients with intact data of HBV genotyping, DNA sequencing, and serological parameters were studied. Nucleotides with the highest frequencies in HBV genotypes B and C from all ASCs were treated as wild-type nucleotides.


RESULTS
Mutations at nt.1674, nt.1719, nt.1762, nt.1764, nt.1846, nt.1896, and nt.1913 in genotype C were significantly associated with CHB, cirrhosis, and HCC, as compared with ASCs. C1673T, A1726C, A1727T, C1730G, C1766T, T1768A, C1773T, and C1799G in genotype C were significantly associated with cirrhosis compared with the CHB patients, whereas these mutations were inversely associated with HCC compared with the cirrhosis patients. Multivariate regression analyses showed that age, male, abnormal alanine aminotransferase (ALT), T1768A, A1762T/G1764A, and A1846T were independently associated with cirrhosis compared with ASCs and the patients with CHB. Age, abnormal ALT, HBV DNA (≥10(4) copies/ml), genotype C, C1653T, T1674C/G, T1753V, and A1762T/G1764A were independently associated with HCC compared with those without HCC. Haplotypic carriages with two or more HBV mutations were significantly associated with HCC. T1674C/G, C1653T, and T1753V were specific for HCC. A1762T/G1764A had a moderate sensitivity and specificity for HCC.


CONCLUSIONS
C1673T, A1726C, A1727T, C1730G, C1766T, T1768A, C1773T, and C1799G in genotype C are specific for cirrhosis. A1846T and T1674C/G are novel factors independently associated with cirrhosis and HCC, respectively.
Yin
Jianhua
J
Department of Epidemiology, Second Military Medical University, Shanghai, China.
Xie
Jiaxin
J
Liu
Shijian
S
Zhang
Hongwei
H
Han
Lei
L
Lu
Wenying
W
Shen
Qiuxia
Q
Xu
Guozhang
G
Dong
Hongjun
H
Shen
Jie
J
Zhang
Jun
J
Han
Jiankang
J
Wang
Lin
L
Liu
Yan
Y
Wang
Fan
F
Zhao
Jun
J
Zhang
Qian
Q
Ni
Wu
W
Wang
Hongyang
H
Cao
Guangwen
G
D000293:Adolescent; D000328:Adult; D017677:Age Distribution; D000704:Analysis of Variance; D006528:Carcinoma, Hepatocellular / Q000453:epidemiology / Q000235:genetics*; D002353:Carrier State / Q000453:epidemiology; D002681:China / Q000453:epidemiology; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005260:Female; D005838:Genotype; D006514:Hepatitis B Surface Antigens / Q000235:genetics; D006515:Hepatitis B virus / Q000235:genetics*; D019694:Hepatitis B, Chronic / Q000453:epidemiology / Q000235:genetics*; D006801:Humans; D016014:Linear Models; D008103:Liver Cirrhosis / Q000453:epidemiology / Q000235:genetics* / Q000821:virology; D008113:Liver Neoplasms / Q000453:epidemiology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009154:Mutation; D016017:Odds Ratio; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D012016:Reference Values; D012720:Severity of Illness Index; D017678:Sex Distribution; D013997:Time Factors; D019562:Viral Load; D055815:Young Adult
D006514:Hepatitis B Surface Antigens