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

Background/Aims
The 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.
Methods
One 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.
Results
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 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.
Conclusions
To 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.

研究背景与目的
乙型肝炎病毒（hepatitis B virus, HBV）表面抗原（HBsAg）的血清学清除被视为慢性乙型肝炎（chronic hepatitis B, CHB）的功能性治愈标准，尽管该现象较为罕见。近期多项全基因组关联研究（genome-wide association studies, GWASs）揭示了与HBV感染临床进程相关的多种遗传变异。然而，上述研究均聚焦于HBV感染向慢性化进展的过程，且由于HBV基因型的异质性，其应用范围受限。本研究旨在针对病毒基因型均一的慢性乙型肝炎患者，探寻与HBsAg血清学清除相关的易感遗传标记物。
研究方法
本研究共纳入200例慢性乙型肝炎患者，其中100例为60岁前实现HBsAg血清学清除者，另100例为年满60岁后仍维持高血清HBsAg水平者。采用极端表型全基因组关联研究对受试者的血液样本开展分析。
研究结果
本研究鉴定出3个单核苷酸多态性（single nucleotide polymorphisms, SNPs）位点，分别为位于11q12.1区域的rs7944135（P = 4.17 × 10−6，比值比[odds ratio, OR] = 4.16，95%置信区间[confidence interval, CI] = 2.27–7.63）、位于5q14.1区域的rs171941（P = 3.52×10−6，OR = 3.69，95% CI = 2.13–6.42），以及位于7p15.2区域的rs6462008（P = 3.40×10−6，OR = 0.34，95% CI = 0.22–0.54），上述位点均为与慢性乙型肝炎患者HBsAg血清学清除相关的全新易感位点。上述位点的侧翼基因包括MPEG1、DTX4、MTX3及HOXA13，被认为具有功能学意义。此外，通过功能分析推测CXCL13也与该过程相关。
研究结论
据我们所知，本研究是首个针对慢性乙型肝炎患者HBsAg血清学清除的全基因组关联研究。本研究鉴定出与慢性乙型肝炎治愈相关的全新易感位点，为其病理生理机制提供了新的研究视角。