Exploratory analysis of HLA variants and occult HBV infection: a multicenter case-control study in Chinese blood donors

Abstract Occult hepatitis B virus infection (OBI), characterized by detectable HBV DNA but undetectable HBsAg, poses diagnostic and clinical challenges, with host genetic factors, particularly HLA-mediated immune regulation, remaining poorly understood. Through whole-exome sequencing of 147 participants (74 OBI cases, 73 chronic HBsAg+ controls), we identified four HLA variants associated with low OBI susceptibility and proposed a dual immune mechanism: Class I variants impair cytotoxic responses, while Class II variants dysregulate humoral immunity. Anti-HBs titers and age modulated genetic risk penetrance, with high anti-HBs increasing OBI susceptibility regardless of genotype, and genetic effects attenuating in individuals >50 years. Integrating HLA variants with serological and baseline characteristics significantly improved OBI susceptibility prediction (AUC 0.93), highlighting the role of HLA-mediated immunity in OBI pathogenesis and the potential of genetic markers for risk stratification in HBV-exposed individuals. Our findings elucidate HLA-mediated immune mechanisms underlying OBI and demonstrate the value of genetic markers in predicting the likelihood of developing OBI or progressing to chronic HBsAg+ status among HBV-exposed individuals.