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

Background & Aims: 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. Approach & Results: 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 (OR meta-analysis =1.33, P meta-analysis =2.6×10 −8 ). Three amino acids within DQβ1 peptide-binding region, HLA-DQβ1Ala13, HLA-DQβ1Tyr26, and HLA-DQβ1Glu45, 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 ( P meta-analysis =3.3×10 −3 ). Conclusions: 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.