Format

Send to

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

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

Tan W1,2, Xia J1,3, Dan Y1,2, Li M4, Lin S5, Pan X6, Wang H3, Tang Y1,2, Liu N1,2, Tan S1,2, Liu M1,2, He W1,2, Zhang W7, Mao Q1,2, Wang Y1,2, Deng G1,2,8.

Author information

1
Department of Infectious Diseases, Southwest Hospital, Third Military Medical University, Chongqing, China.
2
Chongqing Key Laboratory for Research of Infectious Diseases, Chongqing, China.
3
Clinical and Research Center of Liver Failure, The 302nd Hospital, Beijing, China.
4
Department of Infectious Diseases, The 303rd Hospital, Nanning, Guangxi, China.
5
Department of Infectious Diseases, The Affiliated Hospital of Zunyi Medical College, Zunyi, Guizhou, China.
6
Clinical Liver Center, The 180th Hospital, Quanzhou, Fujian, China.
7
Department of Epidemiology and Biostatistics, Imperial College London, London, UK.
8
Institute of Immunology, Third Military Medical University, Chongqing, China.

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 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.

KEYWORDS:

GENETIC POLYMORPHISMS; HEPATITIS B; HLA; LIVER FAILURE

PMID:
28130311
DOI:
10.1136/gutjnl-2016-313035
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center