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Original article
Genome-wide association study identifies HLA-DR variants conferring risk of HBV-related acute-on-chronic liver failure
  1. Wenting Tan1,2,
  2. Jie Xia1,3,
  3. Yunjie Dan1,2,
  4. Mengying Li4,
  5. Shide Lin5,
  6. Xingnan Pan6,
  7. Huifen Wang3,
  8. Yingzi Tang1,2,
  9. Nana Liu1,2,
  10. Shun Tan1,2,
  11. Ming Liu1,2,
  12. Weiwei He1,2,
  13. Weihua Zhang7,
  14. Qing Mao1,2,
  15. Yuming Wang1,2,
  16. Guohong Deng1,2,8
  1. 1Department of Infectious Diseases, Southwest Hospital, Third Military Medical University, Chongqing, China
  2. 2Chongqing Key Laboratory for Research of Infectious Diseases, Chongqing, China
  3. 3Clinical and Research Center of Liver Failure, The 302nd Hospital, Beijing, China
  4. 4Department of Infectious Diseases, The 303rd Hospital, Nanning, Guangxi, China
  5. 5Department of Infectious Diseases, The Affiliated Hospital of Zunyi Medical College, Zunyi, Guizhou, China
  6. 6Clinical Liver Center, The 180th Hospital, Quanzhou, Fujian, China
  7. 7Department of Epidemiology and Biostatistics, Imperial College London, London, UK
  8. 8Institute of Immunology, Third Military Medical University, Chongqing, China
  1. Correspondence to Professor Guohong Deng, Department of Infectious Diseases, Southwest Hospital, Third Military Medical University, 29 Gaotanyan Street, Shapingba District, Chongqing 400038, China; gh_deng{at}hotmail.com

Abstract

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
  • HLA
  • GENETIC POLYMORPHISMS

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Footnotes

  • Correction notice This article has been corrected since it published Online First. The clinical analysis and discussion sections have been updated for clarity.

  • 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.

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