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The genetic polymorphism down‐regulating HLA‐DRB1 enhancer activity facilitates HBV persistence, evolution and hepatocarcinogenesis in the Chinese Han population
Author(s) -
Deng Yang,
Li Peng,
Liu Wenbin,
Pu Rui,
Yang Fan,
Song Jiahui,
Yin Jianhua,
Han Xue,
Li Chengzhong,
Zhao Jun,
Wang Hongyang,
Cao Guangwen
Publication year - 2020
Publication title -
journal of viral hepatitis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.329
H-Index - 100
eISSN - 1365-2893
pISSN - 1352-0504
DOI - 10.1111/jvh.13353
Subject(s) - hepatocellular carcinoma , hepatitis b virus , enhancer , human leukocyte antigen , allele , biology , immunology , genotype , medicine , virology , cancer research , genetics , antigen , gene , virus , gene expression
Abstract 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 at HLA‐DR enhancer 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 between HLA‐DR polymorphisms 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 the HLA‐DRB1 enhancer with rs477515‐T was significantly higher than that with rs477515‐C. The activity of the HLA‐DRB1 enhancer with rs477515‐T and that with rs477515‐C was significantly up‐regulated by interferon‐γ and interleukin‐4, respectively. Interleukin‐6 significantly inhibited the HLA‐DRB1 enhancer 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, possibly via selecting the HCC‐risk HBV mutations. This can be transformed into specific prophylaxis of HCC.