Genome-wide association study identifies HLA-DR variants conferring risk of HBV-related acute-on-chronic liver failure
Genome-wide association study identifies HLA-DR variants conferring risk of HBV-related acute-on-chronic liver failure
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全基因组关联研究确定 HLA-DR 变异会导致 HBV 相关慢加急性肝衰竭的风险
DOI：
10.1136/gutjnl-2016-313035
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发表时间：
2018-04-01
期刊：
影响因子：
24.5
通讯作者：
Deng, Guohong
中科院分区：
文献类型：
--
作者：
Tan, Wenting;Xia, Jie;Deng, Guohong
目的慢性加急性肝衰竭（ACLF）是一个极端的条件后，严重急性加重慢性肝炎B，然而，其发病和进展的潜在遗传因素目前尚不清楚。设计我们进行了全基因组的关联研究399 HBV相关的ACLF（病例）和401无症状的HBV携带者（AsCs，作为对照）无抗病毒治疗。最初的研究结果在四个独立的病例对照组（共901例ACLF和1686例ASCs）中重复。结果在1300例ACLF和2087例AsC中，发现rs3129859位点与HBV相关的ACLF相关（P-显性组合= 2.64 × 10（-20），OR=1.83）。分析确定HLA-DRB 1 *12：02为与ACLF相关的最高易感HLA等位基因（p=3.94x10（-6），OR=2.05）。rs3129859在ACLF亚组（伴有肝硬化的ACLF，p=1.36x10（-16）;不伴有肝硬化的ACLF，p=1.52x10（-7））和低复制期（p=6.36x10（-11），OR=2.29）或HBV e抗原阴性慢性B肝炎期（p=1.51x10（-14），OR=1.86）患者中的相关性很强。ACLF患者的临床特征分析表明，风险rs3129859*C等位基因也与凝血酶原时间延长，腹水的发展和更高的28天mortals.Conclusions我们的全基因组关联研究确定HLA-DR作为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CD 4 + T细胞通路在HBV相关ACLF免疫发病机制中的重要性。
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 P-dominant=2.64x10(-20), OR=1.83). Analysis identified HLA-DRB1*12: 02 as the top susceptible HLA allele associated with ACLF (p=3.94x10(-6), OR=2.05). The association of rs3129859 was robust in ACLF subgroups (ACLFs with liver cirrhosis, p=1.36x10(-16); ACLFs without liver cirrhosis, p=1.52x10(-7)), and patients at low-replicative phase (p=6.36x10(-11), OR=2.29) or HBV e antigen-negative chronic hepatitis B phase (p=1.51x10(-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.