Infectious Disease
Genome wide association analysis in Asian cohorts reveal key variants for spontaneous seroclearance of hepatitis B surface antigen and associated clinical traits Jun Tao* Jun Tao Chien-Jen Chen Zhiwei Liu Hwai-I Yang Kevin Wang Bin Zhu Chih-Jen Huang Yu-Han Huang Mei-Hung Pan Mei-Hsuan Lee
Background: Chronic hepatitis B virus (HBV) infection affects an estimated 16 million individuals worldwide and accounts for approximately 555,000 deaths per year. Seroclearance of hepatitis B surface antigen (HBsAg), which is difficult to achieve with antiviral treatment, is one of the most important clinical outcomes for chronic hepatitis B infection. A prior report has shown that hepatitis B e antigen (HBeAg) positivity, HBV DNA level, and quantitative HBsAg levels are major factors associated with spontaneous HBsAg seroclearance. However, few studies have examined the genetic determinants of spontaneous HBsAg seroclearance. We aimed to evaluate the host genetic basis for spontaneous seroclearance of HBV infection.
Methods: We performed a genome-wide association study (GWAS) of 3,240 individuals with chronic HBV infection who were enrolled between 1991 and 1992 in a community-based study in Taiwan. Serum samples collected at baseline and follow-up examinations were tested for HBsAg, HBeAg, serum HBV DNA levels, and quantitative HBsAg levels. Samples were genotyped using Affymetrix Axiom CHB1 Array arrays and imputed using TOPMed reference panel and a Taiwanese reference panel for the human leukocyte antigen (HLA) regions. A stepwise approach was used to select significant variants – those independently associated with two of the three traits – hepatitis B e antigen (HBeAg) positivity, HBV DNA level, or quantitative HBsAg levels in regression models (P<1×10-5 and LD pruning R2<0.5) – were selected for testing the association of genetic variants with spontaneous HBsAg seroclearance by log-additive analysis, adjusting for sex, age group at baseline, and principal components. To further validate our findings, we examined the impact of identified loci on early clearance of HBsAg in an independent population from the Taiwan Biobank, including 54,072 individuals with HBsAg-negative and anti-HBc-positive status and 11,340 individuals with HBsAg-positive status.
Results: Of 2,951 participants with HBsAg information during an average of 12 years of follow-up, spontaneous HBsAg seroclearance occurred in 535 participants. Four SNPs were associated with two of the three traits (HBeAg positivity, HBV DNA level, or quantitative HBsAg levels), of which three were significantly associated with spontaneous HBsAg seroclearance (i.e., P≤0.05), including rs446717 (nearby gene: CTNNB1; P=0.0508), rs6906021 (HLA-DQB1; P=0.0363), and rs148385846 (CAMK1D; P=0.0047). None of the imputed HLA alleles were significantly associated with spontaneous HBsAg seroclearance. Two loci were also associated with early clearance of HBsAg in the Taiwan Biobank (rs446717; P=0.0417 and rs6906021; P=2.53×10-37).
Conclusion: This study identified three loci that may explain the genetic determinants of spontaneous HBsAg seroclearance through baseline HBeAg positivity, HBV DNA levels, and quantitative HBsAg levels, with two loci also associated with early clearance of HBsAg. Notably, the distinct role of HLA in both early and late HBsAg clearance was observed. These genetic findings may have important clinical implications for treating chronic HBV infections.
