Genome-wide association study identifies HLA-DR variants conferring risk of HBV-related acute-on-chronic liver failure

Gut. 2018 Apr;67(4):757-766. doi: 10.1136/gutjnl-2016-313035. Epub 2017 Jan 27.


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 =2.64×10-20, 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.


Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute-On-Chronic Liver Failure / genetics*
  • Acute-On-Chronic Liver Failure / mortality
  • Adult
  • Alleles
  • Body Mass Index
  • Case-Control Studies
  • Female
  • Genome-Wide Association Study* / methods
  • Genotype
  • HLA-DR Antigens / genetics*
  • Hepatitis B virus
  • Hepatitis B, Chronic
  • Humans
  • Kaplan-Meier Estimate
  • Male
  • Middle Aged
  • Phenotype
  • Polymorphism, Single Nucleotide / genetics


  • HLA-DR Antigens