Contribution of an Asian-prevalent HLA haplotype to the risk of HBV-related hepatocellular carcinoma

Liver cancer, especially HBV (Hepatitis B Virus)-related hepatocellular carcinoma (HCC), is more common in Asian than Caucasian. Regional difference in prevalence of exogenous factors, such as HBV, partially accounts for the fact, however, endogenous factors specific to Asian might also be responsible. HLA (Human Leukocyte Antigen) genes are considered as a candidate due to their high racial diversity. To address this issue, we performed a pan-cancer association study of 147 alleles of HLA class I/II genes (HLA-A, B, and C/DRB1, DQA1, DQB1, DPA1, and DPB1) between 31,727 cases of 12 cancer types, including 1,684 liver cancer cases, and 107,103 controls. HLA alleles consisting a haplotype prevalent in Asian were significantly associated with pan-cancer risk (e.g. odds ratio [OR] for a DRB1*15:02 allele=1.12, p=2.7 x 10-15) and the associations were evidently strong in HBV-related HCC (OR=1.95, p=2.8 x 10-5). In silico prediction suggested that DRB1*15:02 molecule encoded by the haplotype does not efficiently bind HBV-derived peptides. RNA sequencing indicated that HBV-related HCC of the haplotype carriers have low infiltrations of NK cells. These results indicate that Asian-prevalent the HLA haplotype confers HBV-related liver cancer risk by attenuating immune activity against HBV infection and by decreasing NK cell infiltration.