Title: meta-GWAS for inflammatory amplification nodes of acute-on-chronic liver failure in Eastern and Western patients
Funder: The Academy of Medical Sciences

Abstract: Acute-on-Chronic liver failure (ACLF) is a new syndrome distinct from mere acute decompensation, which has a high mortality of 20%-80%. ACLF is prevalent in patients with cirrhotic or chronic but non-cirrhotic liver disease. There is a sharp Eastâ€“West divide with respect to the etiology of ACLF. In Europe, ACLF is observed mainly in patients with alcoholic cirrhosis. In Asia, chronic hepatitis B is a common cause of ACLF in patients with or without cirrhosis. We applied the agnostic approach used in the European CANONIC study to consecutive patients with HBV cirrhosis admitted to 14 university hospitals included in the Chinese Chronic Liver Failure Consortium (Ch.CLIF Consortium). We found the prevalence of extrahepatic organ failures (kidney, heart, brain and respiratory) were remarkably lower and the prevalence of liver and coagulation failures remarkably higher in patient with chronic hepatitis B. It is interesting that almost 50% of the ACLF cases (whoever Western or Eastern patients) are of â€œunknownâ€ origin, the underlying mechanisms explaining a more intense systemic inflammatory response in patients with ACLF relative to patients without are unclear. Clearly, studies are needed to elucidate the mechanisms of systemic inflammation associated with ACLF, in particular in cases in which a trigger cannot be clinically identified. To determine whether there are uniï¬ed amplification steps for the systematic inflammatory response syndrome (SIRS) and compensatory anti-inflammatory response syndrome (CARS) in ACLF patients whoever with or without cirrhosis, a system biological analysis (genomics, immunomics, metabolomics and lipidomics) is inevitably needed. In the past ten years, genome-wide association study (GWAS) has become the dominant strategy for genetic association studies on complex diseases. We had performed a genome-wide association study for HBV-related ACLFs without antiviral treatment. The sentinel SNP rs3129859 seems to confer susceptibility to both ACLF subtypes with or without liver cirrhosis, indicating a shared mechanism underlying the development of these two subtypes of HBV-related ACLF. Here we hypothesize that both Eastern and Western ACLFs share some common genetic loci for inflammatory amplification (SIRS and CARS pathways). At present, we had two independent GWAS data for HBV-related ACLFs, and will get the GWAS data for our ACLF cohorts (discovery cohort and validation cohort) of Chinese CLIF Consortium. Combining with the GWAS data from the EASL-CLIF CANONIC study cohort with unknown origin, we could identify the common nodes involved in genetic susceptibility to inflammatory amplification (intense SIRS/CARS response) of ACLFs.

Lay abstract: Acute-on-chronic liver failure (ACLF) is a new syndrome prevalent in patients with cirrhotic or chronic but non-cirrhotic liver disease. It is a severe syndrome with high mortality and distinct from mere acute decompensation. ACLF brings high health and economic burden both in Western and Eastern countries, however, at present there is no specific therapies available to ACLF. As the underlying mechanisms explaining a more intense systemic inflammatory response in patients with ACLF relative to patients without are unclear, studies are needed to elucidate the mechanisms of systemic inflammation associated with ACLF, in particular in cases in which a trigger cannot be clinically identified. To determine whether there are uniï¬ed amplification steps for the systematic inflammatory response syndrome (SIRS) and compensatory anti-inflammatory response syndrome (CARS) in ACLF patients whoever with or without cirrhosis, a system biological analysis (genomics, immunomics, metabolomics and lipidomics) is performed both for the EASL-CLIF CANONIC cohort and the Chinese-CLIF cohort. Here we hypothesize that both Eastern and Western ACLFs share certain common genetic loci for inflammatory amplification (SIRS and CARS pathways). Combining with the GWAS, metabolomics and cytokine spectrum data from the EASL-China CANONIC study cohorts with unknown origin, we could identify the common nodes involved in genetic susceptibility to inflammatory amplification (intense SIRS/CARS response) of ACLFs. Through this project, we may find the key targets for the intervention of SIRS/CARS steps, then improve the specific prevention and treatment strategies for ACLF in the future.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: ORAL AND GASTROINTESTINAL