title: Genome-wide association study identiﬁes HLA-DR variants conferring risk of HBV-related acute-on-chronic liver failure.
abstract: 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.
  
  
  
  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.
  
  
  
  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 identiﬁedHLA-DRB1*12:02as 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.
  
  
  
  Our genome-wide association study identifiedHLA-DRas 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.
authors.affiliation: Department of Infectious Diseases, Southwest Hospital, Third Military Medical University, Chongqing, China.|Chongqing Key Laboratory for Research of Infectious Diseases, Chongqing, China.
authors.forename: Wenting
authors.initials: W
authors.lastname: Tan
authors.affiliation: Department of Infectious Diseases, Southwest Hospital, Third Military Medical University, Chongqing, China.|Clinical and Research Center of Liver Failure, The 302nd Hospital, Beijing, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Xia
authors.affiliation: Department of Infectious Diseases, Southwest Hospital, Third Military Medical University, Chongqing, China.|Chongqing Key Laboratory for Research of Infectious Diseases, Chongqing, China.
authors.forename: Yunjie
authors.initials: Y
authors.lastname: Dan
authors.affiliation: Department of Infectious Diseases, The 303rd Hospital, Nanning, Guangxi, China.
authors.forename: Mengying
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Infectious Diseases, The Affiliated Hospital of Zunyi Medical College, Zunyi, Guizhou, China.
authors.forename: Shide
authors.initials: S
authors.lastname: Lin
authors.affiliation: Clinical Liver Center, The 180th Hospital, Quanzhou, Fujian, China.
authors.forename: Xingnan
authors.initials: X
authors.lastname: Pan
authors.affiliation: Clinical and Research Center of Liver Failure, The 302nd Hospital, Beijing, China.
authors.forename: Huifen
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Infectious Diseases, Southwest Hospital, Third Military Medical University, Chongqing, China.|Chongqing Key Laboratory for Research of Infectious Diseases, Chongqing, China.
authors.forename: Yingzi
authors.initials: Y
authors.lastname: Tang
authors.affiliation: Department of Infectious Diseases, Southwest Hospital, Third Military Medical University, Chongqing, China.|Chongqing Key Laboratory for Research of Infectious Diseases, Chongqing, China.
authors.forename: Nana
authors.initials: N
authors.lastname: Liu
authors.affiliation: Department of Infectious Diseases, Southwest Hospital, Third Military Medical University, Chongqing, China.|Chongqing Key Laboratory for Research of Infectious Diseases, Chongqing, China.
authors.forename: Shun
authors.initials: S
authors.lastname: Tan
authors.affiliation: Department of Infectious Diseases, Southwest Hospital, Third Military Medical University, Chongqing, China.|Chongqing Key Laboratory for Research of Infectious Diseases, Chongqing, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Infectious Diseases, Southwest Hospital, Third Military Medical University, Chongqing, China.|Chongqing Key Laboratory for Research of Infectious Diseases, Chongqing, China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: He
authors.affiliation: Department of Epidemiology and Biostatistics, Imperial College London, London, UK.
authors.forename: Weihua
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Infectious Diseases, Southwest Hospital, Third Military Medical University, Chongqing, China.|Chongqing Key Laboratory for Research of Infectious Diseases, Chongqing, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Mao
authors.affiliation: Department of Infectious Diseases, Southwest Hospital, Third Military Medical University, Chongqing, China.|Chongqing Key Laboratory for Research of Infectious Diseases, Chongqing, China.
authors.forename: Yuming
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Infectious Diseases, Southwest Hospital, Third Military Medical University, Chongqing, China.|Chongqing Key Laboratory for Research of Infectious Diseases, Chongqing, China.|Institute of Immunology, Third Military Medical University, Chongqing, China.
authors.forename: Guohong
authors.initials: G
authors.lastname: Deng
mesh_terms: D065290:Acute-On-Chronic Liver Failure / Q000235:genetics* / Q000401:mortality; D000328:Adult; D000483:Alleles; D015992:Body Mass Index; D016022:Case-Control Studies; D005260:Female; D055106:Genome-Wide Association Study / Q000379:methods; D005838:Genotype; D006684:HLA-DR Antigens / Q000235:genetics*; D006515:Hepatitis B virus; D019694:Hepatitis B, Chronic; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics
chemical_list: D006684:HLA-DR Antigens
keywords: GENETIC POLYMORPHISMS; HEPATITIS B; HLA; LIVER FAILURE