Objective Acute-on-chronic liver failure (ACLF) is an extreme condition after severe acute exacerbation of chronic hepatitis B; however, the underlying genetic factors involved in its onset and progression are currently unclear. Design We carried out a genome-wide association study among 399 HBV-related ACLFs (cases) and 401 asymptomatic HBV carriers (AsCs, as controls) without antiviral treatment. The initial findings were replicated in four independent case–control sets (a total of 901 ACLFs and 1686 AsCs). The roles of risk variants on clinical traits of ACLF were also analysed. Results Among 1300 ACLFs and 2087 AsCs, we identified rs3129859 at human leucocyte antigen (HLA) class II region (chromosome 6p21.32) associated with HBV-related ACLF (combined Pdominant=2.64×10−20, OR=1.83). Analysis identified HLA-DRB1*12:02 as the top susceptible HLA allele associated with ACLF (p=3.94×10−6, OR=2.05). The association of rs3129859 was robust in ACLF subgroups (ACLFs with liver cirrhosis, p=1.36×10−16; ACLFs without liver cirrhosis, p=1.52×10−7), and patients at low-replicative phase (p=6.36×10−11, OR=2.29) or HBV e antigen-negative chronic hepatitis B phase (p=1.51×10−14, OR=1.86). Clinical traits analysis in patients with ACLF showed that the risky rs3129859*C allele was also associated with prolonged prothrombin time, faster progression to ascites development and higher 28-day mortality. Conclusions Our genome-wide association study identified HLA-DR as the major locus for susceptibility to HBV-related ACLF. Our findings highlight the importance of HLA class II restricted CD4+ T-cell pathway on the immunopathogenesis of HBV-related ACLF.

中文翻译：

---

全基因组关联研究确定了 HLA-DR 变异导致 HBV 相关的急性慢性肝衰竭风险

目的 急性慢性肝衰竭 (ACLF) 是慢性乙型肝炎严重急性加重后的一种极端情况；然而，其发病和进展所涉及的潜在遗传因素目前尚不清楚。设计 我们在没有抗病毒治疗的 399 名 HBV 相关 ACLF（病例）和 401 名无症状 HBV 携带者（AsC，作为对照）中进行了全基因组关联研究。最初的发现在四个独立的病例对照集（总共 901 个 ACLF 和 1686 个 AsC）中得到了复制。还分析了风险变异对 ACLF 临床特征的作用。结果在1300个ACLFs和2087个AsCs中，我们在与HBV相关ACLF相关的人类白细胞抗原（HLA）II类区域（染色体6p21.32）鉴定了rs3129859（组合Pdominant=2.64×10-20，OR=1.83）。分析确定 HLA-DRB1*12：02 作为与 ACLF 相关的最易感 HLA 等位基因（p=3.94×10-6，OR=2.05）。rs3129859 与 ACLF 亚组（有肝硬化的 ACLF，p=1.36×10-16；无肝硬化的 ACLF，p=1.52×10-7）和低复制期患者（p=6.36×10 -11，OR=2.29）或HBV e抗原阴性慢性乙型肝炎期（p=1.51×10-14，OR=1.86）。ACLF 患者的临床特征分析表明，危险的 rs3129859*C 等位基因还与凝血酶原时间延长、腹水发展速度加快和 28 天死亡率升高有关。结论我们的全基因组关联研究确定 HLA-DR 是 HBV 相关 ACLF 易感性的主要位点。我们的研究结果强调了 HLA II 类限制性 CD4+ T 细胞通路对 HBV 相关 ACLF 免疫发病机制的重要性。