Genetic Determinants of Spontaneous Hepatitis B Surface Antigen Seroclearance and Its Associated Viral Markers.

BACKGROUND

Chronic hepatitis B virus (HBV) rarely leads to spontaneous hepatitis B surface antigen (HBsAg) seroclearance. However, host genetics contributing to this outcome remain poorly understood. We investigate genetic variants associated with HBsAg seroclearance and related viral markers.

METHODS

We conducted GWAS in 3240 REVEAL-HBV participants to identify SNPs/HLA variants associated with HBV DNA load, hepatitis B e antigen (HBeAg) seropositivity, and HBsAg level. Variants with suggestively pleiotropic effects (p < 1 × 10-5) were tested for association with spontaneous HBsAg seroclearance. The top variants (p < 0.05) were evaluated in an independent Taiwan Biobank (TWB) cohort, comprising 11,340 HBsAg-positive participants and 54,072 HBsAg-negative but anti-hepatitis B core antigen (anti-HBc) positive participants.

RESULTS

Among 535 spontaneous seroclearance and 2416 chronic HBV carriers in the REVEAL-HBV cohort, we identified 91 SNPs through viral biomarkers. After linkage disequilibrium pruning, four candidates were tested for spontaneous seroclearance, among which two SNPs were significantly associated with seroclearance (rs148385846; nearby gene: CAMK1D; OR = 0.60, p = 0.0047, and rs6906021; nearby gene: HLA-DQB1; OR = 1.15, 95% CI = 1.01-1.32, p = 0.0363); and one (rs446717; nearby gene: CTNNB1) showed a marginal effect (OR = 1.15, 95% CI = 1.00-1.31, p = 0.0508). In TWB, associations for rs6906021 (OR = 1.22, 95% CI = 1.19-1.26, p = 2.53 × 10-37) and rs446717 (OR = 1.03, 95% CI = 1.00-1.06, p = 0.04) were observed for early HBsAg seroclearance.

CONCLUSIONS

Although host genetic factors may influence HBV replication through immune-mediated mechanisms, their impact on HBsAg levels is limited by its dual origin from cccDNA and integrated HBV DNA. These findings enhance understanding of host genetic contributions to HBV traits, though further research is needed to clarify their role in HBsAg seroclearance and guiding immunomodulatory therapies.