HLA-DQB1*06:02 and a critical amino acid variant in protection against occult hepatitis B virus infection.

The human leukocyte antigen (HLA) system plays a critical role in determining the outcomes of hepatitis B virus (HBV) infection, yet the genetic mechanisms underlying occult HBV infection (OBI), a form marked by detectable HBV DNA in the absence of hepatitis B surface antigen, remain poorly defined. Here, we performed high-resolution HLA genotyping and amino acid-based association analysis in a Chinese population comprising 239 OBI cases and 545 healthy controls. We identified the HLA class II allele DQB1*06:02 as a protective signal against OBI, with conditional analysis confirming its independent effect. This allele is carried on the conserved haplotype DRB1*15:01~DQA1*02:01~DQB1*06:02, which was significantly underrepresented in OBI cases. Conversely, the DRB1*09:01~DQA1*03:02~DQB1*03:03 haplotype was associated with increased OBI risk. Analysis of the HLA-DQB1 amino acid residues revealed that position 119, located in an α-helix of the peptide-binding groove, drives a substantial portion of the observed association. The phenylalanine variant at this site remained strongly protective after multiple-testing correction and is encoded by DQB1*06:02. Our study thus delineates both allele and amino acid level HLA determinants of OBI susceptibility, highlighting a key structural residue that may influence antigen presentation and immune clearance of HBV. These findings provide a refined genetic framework for understanding host and virus interactions in occult HBV persistence.