Human Leukocyte Antigen Genotypes Affect Hepatitis B Virus Mutations Associated With Hepatocellular Carcinoma

Masaya Sugiyama¹, Nao Nishida^{1

2}, Seik-Soon Khor^{3

4}, Tadasu Shin-I¹, Keisuke Hino^{5

6}, Masao Honda⁷, Shuichi Kaneko⁷, Hiroshi Yatsuhashi⁸, Kazuhiko Koike⁹, Masayuki Kurosaki¹⁰, Namiki Izumi¹⁰, Yasuhito Tanaka¹¹, Kazumoto Murata¹², Jong-Hon Kang¹³, Eiji Tanaka¹⁴, Akinobu Taketomi¹⁵, Yuichiro Eguchi¹⁶, Goki Suda¹⁷, Naoya Sakamoto¹⁷, Kazuhide Yamamoto¹⁸, Akihiro Tamori¹⁹, Shuhei Hige²⁰, Yoshito Itoh²¹, Satoshi Mochida²², Eiji Mita²³, Tatsuya Ide²⁴, Yoichi Hiasa²⁵, Masahiko Watanabe²⁶, Ken Yamamoto²⁷, Aiko Sakai¹, Takaji Wakita²⁸, Masashi Mizokami³, Katsushi Tokunaga³

Affiliations

¹ Department of Viral Pathogenesis and Controls, National Institute of Global Health and Medicine, Japan Institute for Health Security, Ichikawa, Japan.
² Department of Genomic Function and Diversity, Institute of Integrated Research, Institute of Science Tokyo, Tokyo, Japan.
³ Genome Medical Sciences Project, National Institute of Global Health and Medicine, Japan Institute for Health Security, Tokyo, Japan.
⁴ Singapore Centre for Environmental Life Sciences Engineering, Nanyang Technological University, Singapore, Singapore.
⁵ Department of Gastroenterology and Hepatology, Kawasaki Medical School, Kurashiki, Japan.
⁶ Shunan Memorial Hospital, Kudamatsu, Japan.
⁷ Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Japan.
⁸ NHO Nagasaki Medical Center, Nagasaki, Japan.
⁹ Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
¹⁰ Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan.
¹¹ Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
¹² Division of Virology, Department of Infection and Immunity, Jichi Medical University, Shimotsuke, Japan.
¹³ Center for Gastroenterology, Teine Keijinkai Hospital, Sapporo, Japan.
¹⁴ Nagano University of Health and Medicine, Nagano, Japan.
¹⁵ Department of Gastroenterological Surgery I, Hokkaido University Hospital, Sapporo, Japan.
¹⁶ Loco Medical Group, Loco Medical General Institute, Saga, Japan.
¹⁷ Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
¹⁸ Department of Internal Medicine, Okayama Saiseikai General Hospital, Okayama, Japan.
¹⁹ Department of Hepatology, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan.
²⁰ Department of Gastroenterology, Sapporo Kosei General Hospital, Sapporo, Japan.
²¹ Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
²² Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, Moroyama, Japan.
²³ Department of Gastroenterology and Hepatology, NHO Osaka National Hospital, Osaka, Japan.
²⁴ Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan.
²⁵ Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Japan.
²⁶ Department of Surgery, Kitasato University Kitasato Institute Hospital, Tokyo, Japan.
²⁷ Department of Medical Biochemistry, Kurume University School of Medicine, Kurume, Japan.
²⁸ Japan Institute for Health Security, Tokyo, Japan.

PMID: 40728240
DOI: 10.1111/hepr.70007

Human Leukocyte Antigen Genotypes Affect Hepatitis B Virus Mutations Associated With Hepatocellular Carcinoma

Masaya Sugiyama et al. Hepatol Res. 2025.

. 2025 Jul 29.

doi: 10.1111/hepr.70007. Online ahead of print.

Authors

Affiliations

¹ Department of Viral Pathogenesis and Controls, National Institute of Global Health and Medicine, Japan Institute for Health Security, Ichikawa, Japan.
² Department of Genomic Function and Diversity, Institute of Integrated Research, Institute of Science Tokyo, Tokyo, Japan.
³ Genome Medical Sciences Project, National Institute of Global Health and Medicine, Japan Institute for Health Security, Tokyo, Japan.
⁴ Singapore Centre for Environmental Life Sciences Engineering, Nanyang Technological University, Singapore, Singapore.
⁵ Department of Gastroenterology and Hepatology, Kawasaki Medical School, Kurashiki, Japan.
⁶ Shunan Memorial Hospital, Kudamatsu, Japan.
⁷ Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Japan.
⁸ NHO Nagasaki Medical Center, Nagasaki, Japan.
⁹ Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
¹⁰ Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan.
¹¹ Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
¹² Division of Virology, Department of Infection and Immunity, Jichi Medical University, Shimotsuke, Japan.
¹³ Center for Gastroenterology, Teine Keijinkai Hospital, Sapporo, Japan.
¹⁴ Nagano University of Health and Medicine, Nagano, Japan.
¹⁵ Department of Gastroenterological Surgery I, Hokkaido University Hospital, Sapporo, Japan.
¹⁶ Loco Medical Group, Loco Medical General Institute, Saga, Japan.
¹⁷ Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
¹⁸ Department of Internal Medicine, Okayama Saiseikai General Hospital, Okayama, Japan.
¹⁹ Department of Hepatology, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan.
²⁰ Department of Gastroenterology, Sapporo Kosei General Hospital, Sapporo, Japan.
²¹ Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
²² Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, Moroyama, Japan.
²³ Department of Gastroenterology and Hepatology, NHO Osaka National Hospital, Osaka, Japan.
²⁴ Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan.
²⁵ Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Japan.
²⁶ Department of Surgery, Kitasato University Kitasato Institute Hospital, Tokyo, Japan.
²⁷ Department of Medical Biochemistry, Kurume University School of Medicine, Kurume, Japan.
²⁸ Japan Institute for Health Security, Tokyo, Japan.

PMID: 40728240
DOI: 10.1111/hepr.70007

Abstract

Background and aims: Various viral mutations have been reported to influence disease pathogenesis in infectious diseases. However, these mutations may remain undetected due to patient population changes. Although many causes have been proposed, the exact reasons remain unclear. This study analyzed viral mutations linked to hepatocellular carcinoma (HCC) in patients with hepatitis B by comparing factors between condition-matched patient groups of different human leukocyte antigen (HLA) genotypes.

Methods: HLA genotypes of 2281 healthy individuals, 370 patients with hepatitis B virus (HBV)-derived HCC, and 408 patients with chronic hepatitis B were analyzed to identify HLA genotypes associated with HCC development. Patients with HCC were grouped by HLA-DPB1 genotype to identify HBV genomic variants linked to HCC.

Results: The HLA-DPB1*02:01, 04:01, and 04:02 alleles suppressed chronic hepatitis B (CHB) and HCC development (P = 4.53 × 10^-9, 3.20 × 10^-3, and 3.03 × 10^-4, respectively). Conversely, HLA-DPB1*05:01 and 09:01 alleles were significantly associated with CHB and HCC development (P = 1.01 × 10^-7, 6.51 × 10^-8, respectively). Among HLA-DPB1*02:01 patients, the S166L amino acid (AA) mutation in the PreS/S region of the HBV genome was significantly identified. HLA-DPB1*05:01 homozygous patients significantly had K130M/V131I AA mutations in the X region of the HBV genome, whereas HLA-DPB1*05:01-09:01 heterozygous patients significantly had the H94Y AA mutation in the X region. Stratification by HLA genotype changed the mutation position and strengthened the odds ratios for developing HCC due to viral mutations.

Conclusions: Our analysis revealed that viral mutations associated with HCC vary by HLA genotype. These findings suggest a host-pathogen genetic interaction. HLA genotype stratification may aid in advancing personalized genomic medicine, which has been challenging to apply to chronic diseases.

Keywords: HBV mutation; HLA allele; hepatitis B virus; hepatocellular carcinoma.

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References

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Human Leukocyte Antigen Genotypes Affect Hepatitis B Virus Mutations Associated With Hepatocellular Carcinoma

Affiliations

Human Leukocyte Antigen Genotypes Affect Hepatitis B Virus Mutations Associated With Hepatocellular Carcinoma

Authors

Affiliations

Abstract

References

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