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.
- HEPATITIS B
- LIVER FAILURE
- GENETIC POLYMORPHISMS
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Contributors WT, JX, QM, YW and GD designed the study. WT, JX, ML, SL, XP, HW, YD, ST and ML collected the clinical samples and data. WT, WZ and GD led the data analysis. NL and WH observed the expression of human leucocyte antigen class II molecules on dendritic cells. YT sequenced HBV of dataset 2. WT and GD wrote the manuscript, with contributions from all the authors. GD get the funding for the study. YW and QM supervised the study.
Funding The National Natural Science Foundation of China. Grant No. 81330038; the Chinese State Key Project Specialized for Infectious Diseases. Grant no. 2012ZX10002007-002-005; the Chongqing Natural Science Foundation. Grant no. CSTC-2011JJJQ10005; the Third Military Medical University Key Project for Clinical Research. Grant no. 2012XLC05.
Competing interests None declared.
Patient consent Obtained.
Ethics approval The ethics committee of Southwest Hospital (Chongqing, China).
Provenance and peer review Not commissioned; externally peer reviewed.