Wenting Tan1,2, Jie Xia1,3, Yunjie Dan1,2, Mengying Li4, Shide Lin5, Xingnan Pan6, Huifen Wang3, Yingzi Tang1,2, Nana Liu1,2, Shun Tan1,2, Ming Liu1,2, Weiwei He1,2, Weihua Zhang7, Qing Mao1,2, Yuming Wang1,2, Guohong Deng1,2,8. 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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
Authors: Jonel Trebicka; Alex Amoros; Carla Pitarch; Esther Titos; José Alcaraz-Quiles; Robert Schierwagen; Carmen Deulofeu; Javier Fernandez-Gomez; Salvatore Piano; Paolo Caraceni; Karl Oettl; Elsa Sola; Wim Laleman; Jane McNaughtan; Rajeshwar P Mookerjee; Minneke J Coenraad; Tania Welzel; Christian Steib; Rita Garcia; Thierry Gustot; Miguel A Rodriguez Gandia; Rafael Bañares; Agustin Albillos; Stefan Zeuzem; Victor Vargas; Faouzi Saliba; Frederic Nevens; Carlo Alessandria; Andrea de Gottardi; Heinz Zoller; Pere Ginès; Tilman Sauerbruch; Alexander Gerbes; Rudolf E Stauber; Mauro Bernardi; Paolo Angeli; Marco Pavesi; Richard Moreau; Joan Clària; Rajiv Jalan; Vicente Arroyo Journal: Front Immunol Date: 2019-03-19 Impact factor: 7.561