title: The NFKB1 promoter polymorphism (-94ins/delATTG) alters nuclear translocation of NF-κB1 in monocytes after lipopolysaccharide stimulation and is associated with increased mortality in sepsis.
abstract: BACKGROUND
  Because the nuclear factor-κB (NF-κB) coupled pathway is believed to amplify inflammation prevailing in sepsis, the authors tested the hypotheses that the insertion-deletion polymorphism (-94ins/delATTG) (1) alters nuclear translocation of nuclear factor-κB and activator protein-1 (NF-κB1) in monocytes after lipopolysaccharide stimulation; (2) affects lipopolysaccharide-induced NF-κB1 messenger RNA expression, tumor necrosis factor α concentrations, and tissue factor activity; and (3) may be associated with increased 30-day mortality in patients with sepsis.
  
  
  METHODS
  Nuclear translocation of NF-κB1 in monocytes after lipopolysaccharide stimulation from healthy blood donors was performed with immunofluorescence staining (n = 5 each). Lipopolysaccharide-induced NF-κB1 messenger RNA expression was measured with real-time polymerase chain reaction (PCR; n = 60), tumor necrosis factor α concentrations with a multiplexing system kit (n = 60), and tissue factor activity with thromboelastometry (n = 105). In a prospective study, multivariate proportional hazard analysis tested 30-day mortality in patients with sepsis (n = 143).
  
  
  RESULTS
  The homozygous deletion genotype compared with the homozygous insertion genotype was associated with a nearly twofold increase in nuclear translocation of NF-κB1 (P = 0.001), a threefold difference in NF-κB1 messenger RNA expression (P = 0.001), and a twofold increase in tissue factor expression (P = 0.021). The deletion allele in adults with severe sepsis was tested as an independent prognostic factor for 30-day mortality (hazard ratio, 2.3; 95% CI, 1.13-4.8; P = 0.022). Mortality was 25% for homozygous insertion genotypes but 41% for combined heterozygous deletion/homozygous deletion genotypes (P = 0.034).
  
  
  CONCLUSIONS
  The deletion allele of the NFκB1 insertion-deletion (-94ins/delATTG) polymorphism is associated with increased 30-day mortality in patients with severe sepsis and increased reaction of the innate immune system.
authors.affiliation: Klinik für Anästhesiologie und Intensivmedizin, Universität Duisburg-Essen, Universitätsklinikum Essen, Essen, Germany. michael.adamzik@uk-essen.de
authors.forename: Michael
authors.initials: M
authors.lastname: Adamzik
authors.forename: Simon
authors.initials: S
authors.lastname: Schäfer
authors.forename: Ulrich H
authors.initials: UH
authors.lastname: Frey
authors.forename: Arne
authors.initials: A
authors.lastname: Becker
authors.forename: Maximiliane
authors.initials: M
authors.lastname: Kreuzer
authors.forename: Sandra
authors.initials: S
authors.lastname: Winning
authors.forename: Stilla
authors.initials: S
authors.lastname: Frede
authors.forename: Jörg
authors.initials: J
authors.lastname: Steinmann
authors.forename: Joachim
authors.initials: J
authors.lastname: Fandrey
authors.forename: Kai
authors.initials: K
authors.lastname: Zacharowski
authors.forename: Winfried
authors.initials: W
authors.lastname: Siffert
authors.forename: Jürgen
authors.initials: J
authors.lastname: Peters
authors.forename: Matthias
authors.initials: M
authors.lastname: Hartmann
mesh_terms: D000483:Alleles; D005260:Female; D017353:Gene Deletion; D006801:Humans; D007249:Inflammation / Q000235:genetics; D008070:Lipopolysaccharides / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009000:Monocytes; D016328:NF-kappa B / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011446:Prospective Studies; D060888:Real-Time Polymerase Chain Reaction; D018805:Sepsis / Q000235:genetics / Q000378:metabolism / Q000401:mortality*; D014178:Translocation, Genetic / Q000235:genetics*
chemical_list: D008070:Lipopolysaccharides; D016328:NF-kappa B