title: Polymorphisms in the IL-1 gene cluster influence systemic inflammation in patients at risk for acute-on-chronic liver failure.
abstract: Acute-on-chronic liver failure (ACLF) in cirrhosis is an increasingly recognized syndrome characterized by acute decompensation, organ failure(s) and high short-term mortality. Recent findings suggest that an overexuberant systemic inflammation plays a primary role in ACLF progression. In this study, we examined whether genetic factors shape systemic immune responses in patients with decompensated cirrhosis. Six single-nucleotide polymorphisms (SNPs) in inflammation-related genes (interleukin [IL]-1 beta [IL-1β], rs1143623; IL-1 receptor antagonist [IL-1ra], rs4251961; IL-10, rs1800871; suppressor of cytokine signaling-3, rs4969170; nucleotide-binding oligomerization domain-containing protein 2, rs3135500; and chemerin chemokine-like receptor 1, rs1878022) were genotyped in 279 patients with cirrhosis with (n = 178) and without (n = 101) ACLF from the CANONIC study of the CLIF consortium. Among these SNPs, we identified two polymorphisms belonging to the IL-1 gene cluster (IL-1β and IL-1ra) in strong association with ACLF. Both SNPs were protective against ACLF; IL-1β (odds ratio [OR], 0.34, 95% confidence interval [CI], 0.13-0.89; P < 0.05) and IL-1ra (OR, 0.58; 95% CI, 0.35-0.95; P < 0.05) under the recessive and overdominant inheritance models, respectively. These protective SNPs translated into reduced circulating levels of IL-1β, IL-1α, IL-6, granulocyte-colony stimulating factor, granulocyte-macrophage colony-stimulating factor, and C-reactive protein at enrollment as well as after 7-14 days of admission. These findings were confirmed in vitro in leukocytes incubated with plasma from patients with decompensated cirrhosis carrying the protective SNP genotypes. Notably, a higher frequency of the protective genotypes was observed in patients without (80%) than in those with (20%) ACLF. Consistently, patients carrying the combined protective genotypes showed a lower 28-day mortality rate.
  
  
  
  These data identify two common functional polymorphisms in the IL-1 gene cluster, which are associated with the inflammatory process related to development of ACLF. (Hepatology 2017;65:202-216).
authors: Department of Biochemistry and Molecular Genetics (CDB), Hospital Clínic, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain.
authors: José
authors: J
authors: Alcaraz-Quiles
authors: Department of Biochemistry and Molecular Genetics (CDB), Hospital Clínic, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain.|Biomedical Research Networking Center on Liver and Digestive Diseases (CIBERehd).
authors: Esther
authors: E
authors: Titos
authors: Department of Biochemistry and Molecular Genetics (CDB), Hospital Clínic, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain.
authors: Mireia
authors: M
authors: Casulleras
authors: European Foundation for the Study of Chronic Liver Failure (EF-CLIF) and EASL-CLIF Consortium.
authors: Marco
authors: M
authors: Pavesi
authors: Department of Biochemistry and Molecular Genetics (CDB), Hospital Clínic, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain.
authors: Cristina
authors: C
authors: López-Vicario
authors: Department of Biochemistry and Molecular Genetics (CDB), Hospital Clínic, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain.
authors: Bibiana
authors: B
authors: Rius
authors: Department of Biochemistry and Molecular Genetics (CDB), Hospital Clínic, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain.
authors: Aritz
authors: A
authors: Lopategi
authors: University of Berne, Berne, Switzerland.
authors: Andrea
authors: 0000-0002-4401-2340
authors: A
authors: de Gottardi
authors: Innsbruck Medical University, Innsbruck, Austria.
authors: Ivo
authors: I
authors: Graziadei
authors: Aarhus University Hospital, Aarhus, Denmark.
authors: Henning
authors: H
authors: Gronbaek
authors: Biomedical Research Networking Center on Liver and Digestive Diseases (CIBERehd).|Liver Unit, Hospital Clínic, Barcelona, Spain.
authors: Pere
authors: P
authors: Ginès
authors: European Foundation for the Study of Chronic Liver Failure (EF-CLIF) and EASL-CLIF Consortium.
authors: Mauro
authors: M
authors: Bernardi
authors: European Foundation for the Study of Chronic Liver Failure (EF-CLIF) and EASL-CLIF Consortium.
authors: Vicente
authors: V
authors: Arroyo
authors: Department of Biochemistry and Molecular Genetics (CDB), Hospital Clínic, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain.|Biomedical Research Networking Center on Liver and Digestive Diseases (CIBERehd).|Department of Biomedical Sciences, University of Barcelona, Barcelona, Spain.
authors: Joan
authors: J
authors: Clària
mesh_terms: D065290:Acute-On-Chronic Liver Failure / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D006801:Humans; D007249:Inflammation / Q000150:complications / Q000235:genetics*; D007375:Interleukin-1 / Q000235:genetics*; D008103:Liver Cirrhosis / Q000150:complications; D008297:Male; D008875:Middle Aged; D005810:Multigene Family; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
chemical_list: D007375:Interleukin-1