Associations between hepatitis B virus genotype and mutants and the risk of hepatocellular carcinoma.
Associations between hepatitis B virus genotype and mutants and the risk of hepatocellular carcinoma.
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DOI：
10.1093/jnci/djn243
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发表时间：
2008-08-20
期刊：
影响因子：
--
通讯作者：
REVEAL-HBV Study Group
中科院分区：
文献类型：
--
作者：
Yang HI;Yeh SH;Chen PJ;Iloeje UH;Jen CL;Su J;Wang LY;Lu SN;You SL;Chen DS;Liaw YF;Chen CJ;REVEAL-HBV Study Group
肝细胞癌（HCC）的风险随着血清中B型肝炎病毒（HBV）水平（病毒载量）的增加而增加。然而，目前尚不清楚HBV的遗传特征，包括HBV基因型和特定的基因突变，是否有助于HCC的风险。我们研究了与HBV基因型和前C区和基础核心启动子（BCP）区常见变异相关的HCC风险。从1991年1月5日至1992年12月21日，收集了2762名台湾男性和女性的基线血液样本，这些男性和女性的HBV表面抗原血清学阳性，但未被诊断为HCC;通过实时聚合酶链反应检测样本的HBV病毒载量，并通过熔解曲线分析进行基因分型。基线血清HBV DNA水平大于104拷贝/mL的参与者（n = 1526）通过直接测序检测前核心G1896 A和BCP A1762 T/G1764 A突变体。通过随访检查和与国家癌症登记处和死亡证明档案的计算机连接，确定了HCC的事件病例。在调整其他危险因素后，采用考克斯比例风险模型估计与HBV基因型、前C区和BCP突变相关的HCC风险。所有统计学检验均为双侧检验。在33847人年的随访中，共发生153例HCC病例。感染HBV基因型B或C的受试者每10万人年的HCC发病率分别为305.6（95%置信区间[CI] = 236.9至388.1）和785.8（95% CI = 626.8至972.9）。在基线HBV DNA水平至少为104拷贝/mL的受试者中，携带前核心G1896的患者每10万人-年的HCC发病率较高（野生型）变体的那些比具有G1896 A变体的那些更显著。（955.5 [95% CI = 749.0 - 1201.4] vs 269.4 [95% CI = 172.6 - 400.9]），BCP A1762 T/G1764 A双突变体的患者比BCP A1762/G1764患者的患者更易发生突变。（野生型）变异（1149.2 [95% CI = 872.6至1485.6] vs 358.7 [95% CI = 255.1至490.4]）。基因型C与基因型B相比，发生HCC的多变量校正风险比为1.76（95% CI = 1.19至2.61），前核心区G1896 A与野生型相比为0.34（95% CI = 0.21至0.57），BCP A1762 T/G1764 A与野生型相比为1.73（95% CI = 1.13至2.67）。感染C基因型HBV和野生型前C区1896变异体和BCP 1762/1764变异体的受试者风险最高（校正风险比= 2.99，95%CI = 1.57至5.70，P <0.001）。HBV C基因型、BCP和前C区特异性等位基因与HCC的发生风险相关。这些关联与血清HBV DNA水平无关。
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. 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 104 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. 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 104 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). 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.
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DOI：
10.1073/pnas.88.10.4186
发表时间：
1991-05-01
影响因子：
11.1
作者：
BRUNETTO, MR;GIARIN, MM;BONINO, F
通讯作者：
BONINO, F
影响因子：
6.7
作者：
Lin, CL;Liao, LY;Kao, JH
通讯作者：
Kao, JH
影响因子：
120.7
作者：
Chen, CJ;Yang, HI;Iloeje, UH
通讯作者：
Iloeje, UH
影响因子：
5.4
作者：
Buckwold, VE;Xu, ZC;Ou, JH
通讯作者：
Ou, JH
影响因子：
15.9
作者：
Baumert, TF;Rogers, SA;Liang, TJ
通讯作者：
Liang, TJ