The genetic polymorphism down-regulatingHLA-DRB1enhancer activity facilitates HBV persistence, evolution and hepatocarcinogenesis in the Chinese Han population
The genetic polymorphism down-regulatingHLA-DRB1enhancer activity facilitates HBV persistence, evolution and hepatocarcinogenesis in the Chinese Han population
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DOI：
10.1111/jvh.13353
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发表时间：
2020-07-07
影响因子：
2.5
通讯作者：
Cao, Guangwen
中科院分区：
文献类型：
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作者：
Deng, Yang;Li, Peng;Cao, Guangwen
人类白细胞抗原-DR的遗传易感性与接种乙肝病毒疫苗无反应有关。我们试图揭示它们在慢性感染、乙肝病毒演变和肝细胞癌(HCC)发生中的作用。采用定量聚合酶链式反应对4588名受试者的Athla-DREnhancer区基因多态进行了分型。通过测序确定乙肝病毒的突变。采用双荧光素酶活性测定法检测增强子活性。在另一组397例乙肝病毒感染的肝细胞癌患者中，研究了人类白细胞抗原-DR基因多态性与术后预后的关系。变异等位基因(rs3135395-T、rs3135338-C和rs477515-T)与中国患者中乙肝病毒持续存在的风险降低显著相关。Rs3135395-T、rs3135338-C、rs477515-T和rs2395178-G也显著降低了肝癌风险。Rs3135395-T、rs477515-T和rs2395178-G与肝细胞癌高危突变A1762T/G1764A、T1753V和C1653T的发生负相关。变异的基因类型与肝细胞癌危险的乙肝病毒突变的多重相互作用与降低肝细胞癌的风险显著相关。在多变量COX分析中，rs477515-T独立预测预后良好，风险比为0.48(P=0.002)。Rs477515-T的HLADRB1增强子活性显著高于rs477515-C。Rs477515-T和rs477515-C的HLADRB1增强子的活性分别被干扰素-γ和白介素4显著上调。白细胞介素6显著抑制人类白细胞抗原-DRB1增强子活性，这种作用在携带rs477515-T的患者中更为明显。容易下调人类白细胞抗原-DR的基因多态性促进了从Th1到Th2的转变，并促进了肝细胞癌的发展，可能是通过选择有肝细胞癌风险的乙肝病毒突变来实现的。这可以转化为肝细胞癌的特异性预防。
Genetic predisposition of human leucocyte antigen (HLA)-DR has been linked to nonresponse to hepatitis B virus (HBV) vaccination. We sought to reveal their effects on chronic infection and evolution of HBV and development of hepatocellular carcinoma (HCC). Genetic polymorphisms atHLA-DRenhancer regions were genotyped in 4588 participants using quantitative PCR. HBV mutations were determined by sequencing. A dual-luciferase assay was applied to detect the enhancer activity. Associations betweenHLA-DRpolymorphisms and postoperative prognosis were investigated in another cohort of 397 HBV-infected HCC patients. Variant alleles (rs3135395-T, rs3135338-C and rs477515-T) were significantly associated with a decreased risk of HBV persistence in Chinese patients. rs3135395-T, rs3135338-C, rs477515-T and rs2395178-G also significantly decreased HCC risk. rs3135395-T, rs477515-T and rs2395178-G were inversely associated with the generation of A1762T/G1764A, T1753V and C1653T, the HCC-risk HBV mutations. Multiplicative interactions of the variant genotypes with the HCC-risk HBV mutations were significantly associated with a decreased risk of HCC. In multivariate Cox analysis, rs477515-T independently predicted a favourable prognosis, with a hazard ratio of 0.48 (P = .002). The activity of theHLA-DRB1enhancer with rs477515-T was significantly higher than that with rs477515-C. The activity of theHLA-DRB1enhancer with rs477515-T and that with rs477515-C was significantly up-regulated by interferon-gamma and interleukin-4, respectively. Interleukin-6 significantly inhibited theHLA-DRB1enhancer activity, and this effect was more evident in those carrying rs477515-T. Polymorphisms predisposing to down-regulation of HLA-DR facilitate the Th1-to-Th2 transition and promote HCC development, possiblyviaselecting the HCC-risk HBV mutations. This can be transformed into specific prophylaxis of HCC.