Large-scale genome-wide association study identifies HLA class II variants associated with chronic HBV infection: a study from Taiwan Biobank

Abstract

Background Chronic hepatitis B virus (HBV) infection is a great health burden with geographical variations. Aims To explore genetic variants associated with chronic HBV infection. Methods The study included 15 352 participants seropositive for HBV core antibodies in Taiwan Biobank. Among them, 2591 (16.9%) seropositive for HBV surface antigen (HBsAg) were defined as chronic HBV infection. All participants were examined for whole-genome genotyping by Axiom-Taiwan Biobank Array. The human leucocyte antigen (HLA)imputation was performed after identification of the variants within the region. Logistic regressions were used to estimate odds ratios (ORs) with 95% confidence intervals. Correlations of differentHLAallele frequencies with HBsAg seroprevalence were evaluated across worldwide populations by Pearson correlation coefficients. Epitope prediction was performed forHLAalleles using NetMHCIIpan method. Results Located within a cluster of 450 single nucleotide polymorphisms inHLAclass II, rs7770370 (P = 2.73 x 10(-35)) was significantly associated with HBV chronicity (P-corrected < 8.6 x 10(-8)). Imputation analyses showed thatHLA-DPA1*02:02andHLA-DPB1*05:01were associated with chronic HBV, with adjusted ORs of 1.43 (1.09-1.89) and 1.61 (1.29-2.01). These allele frequencies were positively correlated with global HBsAg seroprevalence, with R of 0.75 and 0.62 respectively (P < 0.05).HLA-DRB1*13:02,HLA-DQA1* 01:02andHLA-DQB1*06:09associated with HBV chronicity negatively, with adjusted ORs of 0.31 (0.17-0.58), 0.70 (0.56-0.87) and 0.33 (0.18-0.63). TheseHLAalleles had various binding affinities to the predicted epitopes derived from HBV nucleocapsid protein. Conclusions HLAclass II variants are relevant for chronicity after HBV acquisition.