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Sci Rep. 2018 May 21;8(1):7958. doi: 10.1038/s41598-018-26217-7.

Genome-wide association study identified new susceptible genetic variants in HLA class I region for hepatitis B virus-related hepatocellular carcinoma.

Author information

1
Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. sawai@m.u-tokyo.ac.jp.
2
Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
3
Genome Medical Science Project, National Center for Global Health and Medicine, Ichikawa, Japan.
4
Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan.
5
Epidemiology and Prevention Group, Center for Public Health Sciences, National Cancer Center, Tokyo, Japan.
6
Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
7
Clinical Research Center, National Nagasaki Medical Center, Nagasaki, Japan.
8
Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
9
Division of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan.
10
Center for Gastroenterology, Teine Keijinkai Hospital, Sapporo, Japan.
11
Department of Gastroenterology, Graduate School of Medical Sciences, International University of Health and Welfare, Narita, Japan.
12
Department of Hepatology and Pancreatology, Kawasaki Medical School, Kurashiki, Japan.
13
Department of Medicine, Shinshu University School of Medicine, Matsumoto, Japan.
14
Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine, Sapporo, Japan.
15
Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
16
Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan.
17
Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, Chiba, Japan.
18
Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan.
19
Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
20
Liver center, Saga University Hospital, Saga, Japan.
21
Division of Gastroenterology and Hepatology, Saitama Medical University, Saitama, Japan.
22
Department of Medicine and State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, China.
23
Center of Excellence in Clinical Virology, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.

Abstract

We have performed a genome-wide association study (GWAS) including 473 Japanese HBV (hepatitis B virus)-positive HCC (hepatocellular carcinoma) patients and 516 HBV carriers including chronic hepatitis and asymptomatic carrier individuals to identify new host genetic factors associated with HBV-derived HCC in Japanese and other East Asian populations. We identified 65 SNPs with P values < 10-4 located within the HLA class I region and three SNPs were genotyped in three independent population-based replication sets. Meta-analysis confirmed the association of the three SNPs (rs2523961: OR = 1.73, P = 7.50 × 10-12; rs1110446: OR = 1.79, P = 1.66 × 10-13; and rs3094137: OR = 1.73, P = 7.09 × 10-9). We then performed two-field HLA genotype imputation for six HLA loci using genotyping data to investigate the association between HLA alleles and HCC. HLA allele association testing revealed that HLA-A * 33:03 (OR = 1.97, P = 4.58 × 10-4) was significantly associated with disease progression to HCC. Conditioning analysis of each of the three SNPs on the HLA class I region abolished the association of HLA-A*33:03 with disease progression to HCC. However, conditioning the HLA allele could not eliminate the association of the three SNPs, suggesting that additional genetic factors may exist in the HLA class I region.

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