title: Do common genetic variants in endotoxin signaling pathway contribute to predisposition to alcoholic liver cirrhosis?
abstract: BACKGROUND
  Tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta), produced by endotoxin-activated Kupffer cells, play a key role in the pathogenesis of alcoholic liver cirrhosis (ALC). Alleles TNFA -238A, IL1B -31T and variant IL1RN*2 of repeat polymorphism in the gene encoding the IL-1 receptor antagonist increase production of TNF-alpha and IL-1beta, respectively. Alleles CD14 -159T, TLR4 c.896G and TLR4 c.1196T modify activation of Kupffer cells by endotoxin. We confirmed the published associations between these common variants and genetic predisposition to ALC by means of a large case-control association study conducted on two Central European populations.
  
  
  METHODS
  The study population comprised a Czech sample of 198 ALC patients and 370 controls (MONICA project), and a German sample of 173 ALC patients and 331 controls (KORA-Augsburg), and 109 heavy drinkers without liver disease.
  
  
  RESULTS
  Single locus analysis revealed no significant difference between patients and controls in all tested loci. Diplotype [IL1RN 2/ 2; IL1B -31T+] was associated with increased risk of ALC in the pilot study, but not in the validation samples.
  
  
  CONCLUSIONS
  Although cytokine mediated immune reactions play a role in the pathogenesis of ALC, hereditary susceptibility caused by variants in the corresponding genes is low in Central European populations.
authors.affiliation: Institute for Clinical and Experimental Medicine, Prague, Czech Republic. jan.petrasek@ikem.cz
authors.forename: Jan
authors.initials: J
authors.lastname: Petrásek
authors.forename: Jaroslav A
authors.initials: JA
authors.lastname: Hubácek
authors.forename: Felix
authors.initials: F
authors.lastname: Stickel
authors.forename: Jan
authors.initials: J
authors.lastname: Sperl
authors.forename: Thomas
authors.initials: T
authors.lastname: Berg
authors.forename: Esther
authors.initials: E
authors.lastname: Ruf
authors.forename: H-Erich
authors.initials: HE
authors.lastname: Wichmann
authors.forename: Arne
authors.initials: A
authors.lastname: Pfeufer
authors.forename: Thomas
authors.initials: T
authors.lastname: Meitinger
authors.forename: Pavel
authors.initials: P
authors.lastname: Trunecka
authors.forename: Julius
authors.initials: J
authors.lastname: Spicák
authors.forename: Milan
authors.initials: M
authors.lastname: Jirsa
mesh_terms: D016022:Case-Control Studies; D004731:Endotoxins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D005838:Genotype; D006262:Health; D006801:Humans; D008104:Liver Cirrhosis, Alcoholic / Q000235:genetics* / Q000378:metabolism; D008297:Male; D015398:Signal Transduction
chemical_list: D004731:Endotoxins