The genetic polymorphism down-regulating HLA-DRB1 enhancer activity facilitates HBV persistence, evolution and hepatocarcinogenesis in the Chinese Han population

Yang Deng; Peng Li; Wenbin Liu; Rui Pu; Fan Yang; Jiahui Song; Jianhua Yin; Xue Han; Chengzhong Li; Jun Zhao; Hongyang Wang; Guangwen Cao

doi:10.1111/jvh.13353

The genetic polymorphism down-regulating HLA-DRB1 enhancer activity facilitates HBV persistence, evolution and hepatocarcinogenesis in the Chinese Han population

J Viral Hepat. 2020 Nov;27(11):1150-1161. doi: 10.1111/jvh.13353. Epub 2020 Jul 7.

Authors

Yang Deng¹, Peng Li¹, Wenbin Liu¹, Rui Pu¹, Fan Yang¹, Jiahui Song¹, Jianhua Yin¹, Xue Han², Chengzhong Li³, Jun Zhao⁴, Hongyang Wang^{5

6}, Guangwen Cao^{1

5

6}

Affiliations

¹ Department of Epidemiology, Naval Medical University, Shanghai, China.
² Division of Chronic Diseases, Center for Disease Control and Prevention of Yangpu District, Shanghai, China.
³ Department of Infectious Diseases, Changhai Hospital, Naval Medical University, Shanghai, China.
⁴ Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China.
⁵ Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer, Ministry of Education, Shanghai, China.
⁶ Shanghai Key Laboratory of Hepatobiliary Tumor Biology, Shanghai, China.

PMID: 32568442
DOI: 10.1111/jvh.13353

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.

Keywords: HBV mutation; chronic hepatitis B; hepatocellular carcinoma; human leucocyte antigen class II DR; risk factor.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Carcinoma, Hepatocellular / genetics*
China
Genetic Predisposition to Disease
Genotype
HLA-DRB1 Chains / genetics*
Hepatitis B virus* / pathogenicity
Hepatitis B, Chronic / genetics*
Humans
Liver Neoplasms / genetics*
Polymorphism, Genetic*

Substances

HLA-DRB1 Chains