Identification of novel susceptibility loci associated with hepatitis B surface antigen seroclearance in chronic hepatitis B

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.

Functions and Molecular Mechanisms of Deltex Family Ubiquitin E3 Ligases in Development and Disease

“…Some interacting proteins, such as TNF receptor-associated factor 3-interacting protein 3 (TRAF3IP3) and dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 2 (DYRK2), are also essential for the NLRP4/DTX4 complex to promote TBK1 degradation via Lys48-linked ubiquitination ( An et al, 2015 ; Deng et al, 2020 ). In chronic hepatitis B, the reduction of DTX4 expression partially mediates the IFN-I signaling pathway to increase the sustenance of hepatitis B virus (HBV) and maintenance of hepatitis B surface antigen (HBsAg) in the serum ( Kim et al, 2018 ).…”

“…Hepatic cells DTX4 mediates IFN-I signal to influence HBV sustenance and maintenance of HBsAg in chronic hepatitis B (Kim et al, 2018) with mutations than in those without mutations, suggesting that DTX1 mutations were beneficial for the survival and prognosis of patients with early NSCLC (Lee et al, 2019). In contrast, patients with small cell lung cancer (SCLC) carrying DTX1 mutations showed a worse response to chemotherapy and a lower OS rate, suggesting that mutations in the same gene may play opposite (Nafia et al, 2020) roles in different subtypes of malignant tumors in the same organ.…”

A machine learning-based SNP-set analysis approach for identifying disease-associated susceptibility loci

“…This study aims to identify disease-associated susceptibility loci by augmenting previous GWAS findings using the integration of RF and cluster analysis. The proposed approach was applied to a researchers were able to detect rs2399971, a variant that was not considered to be significantly associated with the phenotype in the main GWAS, but which obtained a significantly low p-value in a subgroup analysis [39]. Results of the association tests conducted on the generated SNP-sets led to the implication of gene LINC00578 and locus 11p15.…”

“…p-values, the set which obtained the highest test statistic is the one composed of rs1809862, rs10769023, rs10838245, rs2017434, rs2047456, rs7945342, and rs872751-all GWAS-identified SNPs [39]. All these variants reside in 11p15.4, a region that shows a possible correlation with HBsAg seroclearance.…”

“…This study used the data provided in [39] which was a project approved by the ethics committees at Korea University Anam Hospital (ED13220) and conducted in agreement with the ethical principles of the Declaration of Helsinki. According to the project's ethical declaration, all patients provided written informed consent for participation and use of their data for research purposes.…”