Zhiwei Liu1, Chih-Jen Huang2, Yu-Han Huang3, Mei-Hung Pan2, Mei-Hsuan Lee3, Kelly J Yu1, Ruth M Pfeiffer1, Mathias Viard4, Yuko Yuki4, Xiaojiang Gao5, Mary Carrington4,6, Chien-Jen Chen2, Allan Hildesheim1, Hwai-I Yang2,3,7. 1. Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, USA. 2. Genomics Research Center, Academia Sinica, Taipei, Taiwan. 3. Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan. 4. Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA. 5. Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA. 6. Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard, Cambridge, Massachusetts, USA. 7. Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
Abstract
BACKGROUND: Diversity in the HLA genes might be associated with disease outcomes-the heterozygote advantage hypothesis. We tested this hypothesis in relation to hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC). METHODS: We utilized DNA from > 10 000 Taiwanese individuals with current or past HBV infection to examine the association between HLA diversity and critical natural history steps in the progression from HBV infection to HCC. Individuals were classified as homozygotes at a given locus when imputed to carry the same 4-digit allele for the 2 HLA alleles at that locus. RESULTS: Increase in number of homozygous HLA class II loci was associated with an increased risk of chronic HBV infection (Ptrend = 1.18 × 10-7). Among chronic HBV carriers, increase in number of homozygous HLA class II loci was also associated with an increased risk of HBV-associated HCC (Ptrend = .031). For individual HLA loci, HLA-DQB1 homozygosity was significantly associated with HCC risk (adjusted hazard ratio = 1.40; 95% confidence interval, 1.06-1.84). We also found that zygosity affects risk of HCC through its ability to affect viral control. CONCLUSIONS: Homozygosity at HLA class II loci, particularly HLA-DQB1, is associated with a higher risk of HBV-associated HCC. Published by Oxford University Press for the Infectious Diseases Society of America 2021.
BACKGROUND: Diversity in the HLA genes might be associated with disease outcomes-the heterozygote advantage hypothesis. We tested this hypothesis in relation to hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC). METHODS: We utilized DNA from > 10 000 Taiwanese individuals with current or past HBV infection to examine the association between HLA diversity and critical natural history steps in the progression from HBV infection to HCC. Individuals were classified as homozygotes at a given locus when imputed to carry the same 4-digit allele for the 2 HLA alleles at that locus. RESULTS: Increase in number of homozygous HLA class II loci was associated with an increased risk of chronic HBV infection (Ptrend = 1.18 × 10-7). Among chronic HBV carriers, increase in number of homozygous HLA class II loci was also associated with an increased risk of HBV-associated HCC (Ptrend = .031). For individual HLA loci, HLA-DQB1 homozygosity was significantly associated with HCC risk (adjusted hazard ratio = 1.40; 95% confidence interval, 1.06-1.84). We also found that zygosity affects risk of HCC through its ability to affect viral control. CONCLUSIONS: Homozygosity at HLA class II loci, particularly HLA-DQB1, is associated with a higher risk of HBV-associated HCC. Published by Oxford University Press for the Infectious Diseases Society of America 2021.
Entities:
Keywords:
Taiwan; cirrhosis; hepatitis B virus; hepatocellular carcinoma; human leukocyte antigen; zygosity