title: A common haplotype of the LBP gene predisposes to severe sepsis.
abstract: OBJECTIVE
  To investigate whether common variants across the LBP gene contribute to the development of severe sepsis. Sepsis is the leading cause of multiple system organ dysfunction and death in critically ill patients. The lipopolysaccharide-binding protein is an acute-phase protein that plays a dominant role in the genesis of sepsis by initiating signal transduction pathways leading to the activation of the inflammatory host response.
  
  
  METHODS
  Prospectively enrolled case-control study of adults with severe sepsis.
  
  
  METHODS
  A network of intensive care units.
  
  
  METHODS
  We enrolled 175 patients meeting international definition criteria for severe sepsis and 357 population-based controls for comparison.
  
  
  METHODS
  Genotyping of the LBP gene was performed and disease association was tested. Serum lipopolysaccharide-binding protein levels were measured in patients and related to genetic variants.
  
  
  RESULTS
  A haplotype window analysis revealed that a common 4-SNP risk haplotype from the 5'-flanking region of the LBP gene, comprising positions -1978 to -763 from the transcription start site, was strongly associated with susceptibility to severe sepsis. Risk haplotype homozygous carriers had an increased risk for severe sepsis (odds ratio = 2.21; 95% confidence interval = 1.39-3.51; unadjusted p < .001; adjusted p < .025). Mean serum lipopolysaccharide-binding protein levels from inclusion to 7th day were significantly higher in homozygous carriers patients (130.1 [102.9-164.5] and 98.9 [79.7-122.8] microg/mL, respectively) than in noncarriers (101.6 [87.9-117.5] and 58.7 [51.4-67.2] microg/mL, respectively) (p = .046).
  
  
  CONCLUSIONS
  This study strongly supports the involvement of LBP gene variants in severe sepsis susceptibility and reinforces the merit of further exploration of the role of lipopolysaccharide-binding protein in sepsis.
authors.affiliation: CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Flores
authors.forename: Lina
authors.initials: L
authors.lastname: Pérez-Méndez
authors.forename: Nicole
authors.initials: N
authors.lastname: Maca-Meyer
authors.forename: Arturo
authors.initials: A
authors.lastname: Muriel
authors.forename: Elena
authors.initials: E
authors.lastname: Espinosa
authors.forename: Jesús
authors.initials: J
authors.lastname: Blanco
authors.forename: Rubén
authors.initials: R
authors.lastname: Sangüesa
authors.forename: Mercedes
authors.initials: M
authors.lastname: Muros
authors.forename: Joe G N
authors.initials: JG
authors.lastname: Garcia
authors.forename: Jesús
authors.initials: J
authors.lastname: Villar
mesh_terms: D018806:APACHE; D000368:Aged; D000483:Alleles; D002352:Carrier Proteins / Q000097:blood / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D006580:Genetic Carrier Screening; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005820:Genetic Testing; D005838:Genotype; D006239:Haplotypes; D017052:Hospital Mortality; D006801:Humans; D007362:Intensive Care Units; D015810:Linkage Disequilibrium; D008137:Longitudinal Studies; D008297:Male; D008565:Membrane Proteins / Q000097:blood / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D018805:Sepsis / Q000097:blood / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality; D016019:Survival Analysis
chemical_list: D002352:Carrier Proteins; D008565:Membrane Proteins; C493339:RAPH1 protein, human