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HLA-DQB1*03:01 and risk of Hepatitis B virus-related hepatocellular carcinoma

  1. Author:
    Zhang, Ting
    Huang, Chih-Jen
    Chen, Hai-Tao
    Huang, Yu-Han
    Pan, Mei-Hung
    Lee, Mei-Hsuan
    Viard,Mathias
    Hildesheim, Allan
    Pfeiffer, Ruth M
    Carrington,Mary
    Chen, Chien-Jen
    Zhu, Bin
    Lenz, Tobias L
    Jiang, Deke
    Yang, Hwai-I
    Liu, Zhiwei

  2. Author Address

    Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA., Genomics Research Center, Academia Sinica, Taipei, Taiwan., State Key Laboratory of Organ Failure Research, MOE Key Laboratory of Infectious Diseases Research in South China, Guangdong Provincial Key Laboratory for Prevention and Control of Major Liver Diseases, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, PR China., School of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen, PR China., Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan., Basic Science Program, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, Maryland, USA., Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA., Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard, Cambridge, Massachusetts, USA., Research Unit for Evolutionary Immunogenomics, Department of Biology, University of Hamburg, Hamburg, Germany., Key Laboratory of Molecular Pathology in Tumors of Guangxi Higher Education Institutions, Department of Pathology, the Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi, PR China., Institute of Clinical Medicine, National Yang-Ming Chiao Tung University, Taipei, Taiwan., Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan., Biomedical Translation Research Center, Academia Sinica, Taipei, Taiwan., Doctoral Program of Clinical and Experimental Medicine, National Sun Yat-Sen University, Kaohsiung, Taiwan.,
    1. Year: 2025
    2. Date: Mar 14
    3. Epub Date: 2025 03 14
  2. Journal: Hepatology (Baltimore, Md.)
  4. Type of Article: Article
  1. Abstract:

    The human leukocyte antigen (HLA) locus is implicated in hepatocellular carcinoma (HCC) among chronic hepatitis B virus (HBV) carriers. We investigated associations of HLA variants, amino acid polymorphisms, zygosity, and evolutionary divergence (HED) with HBV-related HCC in Han Chinese and explored biological mechanisms. We examined the associations of HLA variants (imputed 4-digit classical alleles and amino acid polymorphisms), zygosity, and HED with HBV-related HCC in a discovery set (706 HBV-related HCC cases, 6,197 chronic HBV carriers in Taiwan). Significant signals were validated in independent set (636 cases, 560 controls in Qidong, PR China). We used logistic regression adjusted for sex, age, and top 10 genetic principal components, with a Bonferroni-correction for multiple testing (p< 1.6×10-4). We evaluated predicted peptide-binding affinities and control of viral load, viral population diversity, and inflammatory markers for significant signals. HLA-DQB1*03:01 was most significantly associated with HBV-related HCC in discovery and validation sets (ORmeta-analysis=1.33, Pmeta-analysis=2.6×10-8). Three amino acids within DQß1 peptide-binding region, HLA-DQß1Ala13, HLA-DQß1Tyr26, and HLA-DQß1Glu45, were positively associated with HCC. HLA-DQB1*03:01 was associated with lower binding affinity of HBV nucleocapsid antigen and higher HBV DNA load and serum soluble programmed cell death 1 (sPD-1) (P< 0.05). HLA-DQB1 heterozygosity was inversely associated with HCC independent of HLA-DQB1*03:01 (Pmeta-analysis=3.3×10-3). HLA-DQB1*03:01 and its three key amino acids are associated with an increased HBV-related HCC risk. This association may be explained by the low binding affinity to HBV antigen, resulting in poor control of viral load and increased inflammation, as evidenced by sPD-1 levels. Copyright © 2025 American Association for the Study of Liver Diseases.

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External Sources

  1. View Full Text
  2. DOI: 10.1097/HEP.0000000000001307
  3. PMID: 40084945
  4. PII : 01515467-990000000-01202

Library Notes

  1. Fiscal Year: FY2024-2025
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