Department of Epidemiology, Second Military Medical University, Shanghai.
Department of Microbiology, School of Basic Medical Science, Peking University Health Science Center, Beijing.
Ann Oncol. 2014 Dec;25(12):2413-2419. doi: 10.1093/annonc/mdu451. Epub 2014 Sep 15.
Nonresolving inflammation and viral mutations are important in hepatitis B virus (HBV)-induced hepatocarcinogenesis. However, the effects of genetic polymorphisms affecting nuclear factor-kappaB (NF-κB) on HBV persistence and generation of hepatocellular carcinoma (HCC)-related HBV mutations remain unknown.
rs28362491 (NFKB1 -94Ins > Del), rs2233406 (NFKBIA -826C > T), rs3138053 (NFKBIA -881A > G), and rs696 (NFKBIA +2758G > A) were genotyped in 1342 healthy controls, 327 HBV-clearance subjects, and 3976 HBV-positive subjects including 1495 HCC patients, using quantitative PCR. HBV mutations were determined by sequencing. The NFKBIA promoter activity was assessed by transient transfection. Multiplicative interactions of the polymorphisms and viral mutations were assessed by multivariate logistic regression.
Compared with HBV-clearance subjects, rs2233406 (CT versus CC) and rs3138053 (AG or AG + GG versus AA) significantly decreased HBV persistence, especially in the genotype B HBV-infected subjects. In the genotype C HBV-infected subjects, rs2233406 variant genotypes were significantly associated with an increased risk of HCC [CT versus CC: age-, gender-adjusted odds ratio (AOR), 1.33; 95% confidence interval (CI) 1.01-1.75 in training set and AOR, 1.59; 95% CI 1.01-2.52 in validation set] compared with HCC-free HBV-infected subjects and significantly increased the frequencies of HCC-related HBV mutations (A1762T/G1764A, T1753V, preS1 start codon mutation, and preS deletion); rs28362491 (Del/Del or Ins/Del + Del/Del versus Ins/Ins) significantly increased the frequency of A1762T/G1764A and reduced the frequency of preS2 start codon mutation. The variant genotypes impaired NFKBIA promoter activity in hepatic cells. The interaction of rs2233406 variant genotypes (CT + TT versus CC) with A1762T/G1764A significantly increased HCC risk in genotype C HBV-infected subjects, with AOR of 2.61 (95% CI 1.09-6.26).
Genetic polymorphisms improving NF-κB activity contribute to genotype B HBV clearance. The rs2233406 variant genotypes significantly increase HCC risk, possibly via facilitating immune selection of the HBV mutations. The host-virus interactions are important in identifying HBV-infected subjects who are more likely to develop HCC.
未解决的炎症和病毒突变在乙型肝炎病毒（HBV）诱导的肝癌发生中很重要。然而，影响核因子-κB（NF-κB）的遗传多态性对 HBV 持续存在和产生与肝细胞癌（HCC）相关的 HBV 突变的影响尚不清楚。
采用定量 PCR 方法对 1342 名健康对照者、327 名 HBV 清除者和 3976 名 HBV 阳性者（包括 1495 名 HCC 患者）进行 rs28362491（NFKB1-94Ins > Del）、rs2233406（NFKBIA-826C > T）、rs3138053（NFKBIA-881A > G）和 rs696（NFKBIA+2758G > A）基因分型。通过测序确定 HBV 突变。通过瞬时转染评估 NFKBIA 启动子活性。采用多变量 logistic 回归评估多态性和病毒突变的相乘交互作用。
与 HBV 清除者相比，rs2233406（CT 与 CC）和 rs3138053（AG 或 AG + GG 与 AA）显著降低了 HBV 持续存在，尤其是在基因型 B HBV 感染者中。在基因型 C HBV 感染者中，rs2233406 变异基因型与 HCC 的风险增加显著相关（CT 与 CC：年龄、性别调整后的比值比[OR]，1.33；95%置信区间[CI]，1.01-1.75，在训练集中；OR，1.59；95%CI，1.01-2.52，在验证集中），与无 HCC 的 HBV 感染者相比，并显著增加了与 HCC 相关的 HBV 突变（A1762T/G1764A、T1753V、前 S1 起始密码子突变和前 S 缺失）的频率；rs28362491（Del/Del 或 Ins/Del + Del/Del 与 Ins/Ins）显著增加了 A1762T/G1764A 的频率，并降低了前 S2 起始密码子突变的频率。变异基因型降低了肝细胞中 NFKBIA 启动子的活性。rs2233406 变异基因型（CT + TT 与 CC）与 A1762T/G1764A 的相互作用显著增加了基因型 C HBV 感染者的 HCC 风险，OR 为 2.61（95%CI，1.09-6.26）。
增强 NF-κB 活性的遗传多态性有助于清除基因型 B HBV。rs2233406 变异基因型显著增加 HCC 风险，可能通过促进 HBV 突变的免疫选择。宿主-病毒相互作用在确定更有可能发展为 HCC 的 HBV 感染者方面很重要。
