Antigen presentation by HLA class II molecules to CD4 + T cells is an essential step for generating antibodies to hepatitis B antigens. In this study, we investigated the association between the HLA‐DRB1 gene and the status of antibodies to hepatitis B surface and e antigens. Our results revealed a significant association between the status of anti‐HBsAg and HLA‐DRB1*04:03 (OR = 4.11, 95% CI = 1.50–10.84, p = 0.005, P adj. = 0.05) as well as HLA‐DRB1*15:01 (OR = 1.74, 95% CI = 1.20–2.50, p = 0.002, P adj. = 0.045). MHC II binding predictions and in silico docking demonstrated strong binding affinity of HBsAg peptides to these two HLA‐DRB1 molecules. Conversely, the status of anti‐HBeAg was inversely associated with HLA‐DRB1*14:54 (OR = 0.34, 95% CI = 0.18–0.64, p = 0.001, P adj. = 0.011), and in silico analysis revealed weak binding affinity of HBeAg peptides to HLA‐DRB1*14:54. In conclusion, these findings support the involvement of HLA‐DRB1 in humoral immunity against HBV infection.
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