Abstract
Background/AimsThe seroclearance of hepatitis B virus (HBV) surface antigen (HBsAg) is regarded as a functional cure of chronic hepatitis B (CHB) although it occurs rarely. Recently, several genome-wide association studies (GWASs) revealed various genetic alterations related to the clinical course of HBV infection. However, all of these studies focused on the progression of HBV infection to chronicity and had limited application because of the heterogeneity of HBV genotypes. In the present study, we aimed to determine susceptibility genetic markers for seroclearance of HBsAg in CHB patients with a homogenous viral genotype.MethodsOne hundred patients with CHB who had experienced HBsAg seroclearance before 60 years of age and another 100 with CHB showing high serum levels of HBsAg even after 60 years of age were enrolled. Extreme-phenotype GWAS was conducted using blood samples of participants.ResultsWe identified three single nucleotide polymorphisms, rs7944135 (P = 4.17 × 10−6, odds ratio [OR] = 4.16, 95% confidence interval [CI] = 2.27–7.63) at 11q12.1, rs171941 (P = 3.52×10−6, OR = 3.69, 95% CI = 2.13–6.42) at 5q14.1, and rs6462008 (P = 3.40×10−6, OR = 0.34, 95% CI = 0.22–0.54) at 7p15.2 as novel susceptibility loci associated with HBsAg seroclearance in patients with CHB. The flanking genes at these loci including MPEG1, DTX4, MTX3, and HOXA13 were suggested to have functional significance. In addition, through functional analysis, CXCL13 was also presumed to be related.ConclusionsTo the best of our knowledge, this study is the first GWAS regarding the seroclearance of HBsAg in CHB patients. We identify new susceptibility loci for cure of CHB, providing new insights into its pathophysiology.
Highlights
686,000 people die each year due to severe and advanced liver diseases such as cirrhosis and cancer induced by chronic hepatitis B (CHB) infection [1,2,3]
We identified three single nucleotide polymorphisms, rs7944135 (P = 4.17 × 10−6, odds ratio [OR] = 4.16, 95% confidence interval [CI] = 2.27–7.63) at 11q12.1, rs171941 (P = 3.52×10−6, OR = 3.69, 95% CI = 2.13–6.42) at 5q14.1, and rs6462008 (P = 3.40×10−6, OR = 0.34, 95% CI = 0.22–0.54) at 7p15.2 as novel susceptibility loci associated with hepatitis B surface antigen (HBsAg) seroclearance in patients with CHB
Single-nucleotide polymorphism (SNP) associated with HBsAg clearance in CHB
Summary
686,000 people die each year due to severe and advanced liver diseases such as cirrhosis and cancer induced by chronic hepatitis B (CHB) infection [1,2,3]. In Korea, public vaccination programs have decreased the incidence of hepatitis B virus (HBV) surface antigen (HBsAg) seropositive patients, but the incidence remains as high as 3% of the entire population because of higher carrier rates among the people over 30 years old who did not undergo universal vaccination and presumed to have been at risk of perinatal (vertical) transmission and horizontal transmission in early childhood [4]. HBsAg seroclearance has been recognized as a marker for permanent remission from HBV infection if there is no pre-existing cirrhosis or viral superinfection and designated as a functional cure in current practice guidelines [7]. The rate of HBsAg seroclearance among patients with CHB during clinical management is extremely low worldwide (0.7–1.9% per year)[8,9,10,11,12] and much lower in Korea (0.4% per year) [13], possibly because of differences in prevalent HBV genotype or transmission age [13,14]
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