Associations between hepatitis B virus genotype and mutants and the risk of hepatocellular carcinoma.
BACKGROUND
The risk of hepatocellular carcinoma (HCC) increases with increasing level of hepatitis B virus (HBV) in serum (viral load). However, it is unclear whether genetic characteristics of HBV, including HBV genotype and specific genetic mutations, contribute to the risk of HCC. We examined the HCC risk associated with HBV genotypes and common variants in the precore and basal core promoter (BCP) regions.


METHODS
From January 5, 1991, to December 21, 1992, baseline blood samples were collected from 2762 Taiwanese men and women who were seropositive for HBV surface antigen but had not been diagnosed with HCC; the samples were tested for HBV viral load by real-time polymerase chain reaction and genotyped by melting curve analysis. Participants who had a baseline serum HBV DNA level greater than 10(4) copies/mL (n = 1526) were tested for the precore G1896A and BCP A1762T/G1764A mutants by direct sequencing. Incident cases of HCC were ascertained through follow-up examinations and computerized linkage to the National Cancer Registry and death certification profiles. A Cox proportional hazards model was used to estimate the risk of HCC associated with HBV genotype and precore and BCP mutants after adjustment for other risk factors. All statistical tests were two-sided.


RESULTS
A total of 153 HCC cases occurred during 33 847 person-years of follow-up. The HCC incidence rates per 100 000 person-years for participants infected with HBV genotype B or C were 305.6 (95% confidence interval [CI] = 236.9 to 388.1) and 785.8 (95% CI = 626.8 to 972.9), respectively. Among participants with a baseline HBV DNA level of at least 10(4) copies/mL, HCC incidence per 100 000 person-years was higher for those with the precore G1896 (wild-type) variant than for those with the G1896A variant (955.5 [95% CI = 749.0 to 1201.4] vs 269.4 [95% CI = 172.6 to 400.9]) and for those with the BCP A1762T/G1764A double mutant than for those with BCP A1762/G1764 (wild-type) variant (1149.2 [95% CI = 872.6 to 1485.6] vs 358.7 [95% CI = 255.1 to 490.4]). The multivariable-adjusted hazard ratio of developing HCC was 1.76 (95% CI = 1.19 to 2.61) for genotype C vs genotype B, 0.34 (95% CI = 0.21 to 0.57) for precore G1896A vs wild type, and 1.73 (95% CI = 1.13 to 2.67) for BCP A1762T/G1764A vs wild type. Risk was highest among participants infected with genotype C HBV and wild type for the precore 1896 variant and mutant for the BCP 1762/1764 variant (adjusted hazard ratio = 2.99, 95% CI = 1.57 to 5.70, P < .001).


CONCLUSIONS
HBV genotype C and specific alleles of BCP and precore were associated with risk of HCC. These associations were independent of serum HBV DNA level.
Yang
Hwai-I
HI
Genomics Research Center, Academia Sinica and Graduate Institute of Epidemiology, National Taiwan University, Taipei, Taiwan.
Yeh
Shiou-Hwei
SH
Chen
Pei-Jer
PJ
Iloeje
Uchenna H
UH
Jen
Chin-Lan
CL
Su
Jun
J
Wang
Li-Yu
LY
Lu
Sheng-Nan
SN
You
San-Lin
SL
Chen
Ding-Shinn
DS
Liaw
Yun-Fan
YF
Chen
Chien-Jen
CJ
D000328:Adult; D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000821:virology*; D004279:DNA, Viral / Q000302:isolation & purification; D005260:Female; D005500:Follow-Up Studies; D005787:Gene Frequency; D008040:Genetic Linkage; D005838:Genotype; D006509:Hepatitis B / Q000150:complications* / Q000175:diagnosis; D006514:Hepatitis B Surface Antigens / Q000097:blood; D006515:Hepatitis B virus / Q000235:genetics* / Q000276:immunology / Q000302:isolation & purification*; D006801:Humans; D015994:Incidence; D008113:Liver Neoplasms / Q000821:virology*; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009154:Mutation; D016017:Odds Ratio; D016133:Polymerase Chain Reaction; D016016:Proportional Hazards Models; D012042:Registries; D012107:Research Design; D018570:Risk Assessment; D012307:Risk Factors; D017422:Sequence Analysis, DNA; D013624:Taiwan / Q000453:epidemiology; D019562:Viral Load
D004279:DNA, Viral; D006514:Hepatitis B Surface Antigens