title: Systemic responsiveness to lipopolysaccharide and polymorphisms in the toll-like receptor 4 gene in human beings.
abstract: BACKGROUND
  The response to lipopolysaccharide exposure is highly variable and might be a result of genetic diversity between individuals. The toll-like receptor 4 (TLR-4) is the principal receptor for lipopolysacharide.
  
  
  OBJECTIVE
  We investigated the association between single-nucleotide polymorphisms in the TLR4 locus and levels of systemic inflammatory markers in response to lipopolysaccharide.
  
  
  METHODS
  Healthy subjects (n = 116) were genotyped for the most frequent polymorphisms found in the promoter and coding region of the TLR4 gene (-2026A/T, -1607T/C, +896A/G, and +1196C/T relative to the translation start site). Subjects were challenged with 20 microg lipopolysaccharide by inhalation.
  
  
  RESULTS
  Polymorphisms at +896 and +1196 were in complete linkage disequilibrium, and no homozygotes for the less common allele, G and T respectively, were found. After lipopolysaccharide inhalation, subjects heterozygous for either TLR-4/+896 or TLR4/+1196 had significantly lower numbers of white blood cell counts and lower levels of C-reactive protein and lipopolysaccharide-binding protein compared with homozygotes with the common allele. None of the heterozygous subjects (n = 18) except 1 were high responders to lipopolysaccharide (defined as a rise in C-reactive protein > 10 mg/L), whereas 36 of 98 homozygous subjects were high responders (P <.02). No association was observed between the TLR-4/-2026 and TLR-4/-1607 polymorphisms and lipopolysaccharide responsiveness.
  
  
  CONCLUSIONS
  The single-nucleotide polymorphisms at position +896 or +1196 in the TLR-4 gene is associated with systemic inflammatory hyporesponsiveness to inhaled lipopolysaccharide.
authors: Clinic of Allergology and Respiratory Diseases, CHU Saint-Pierre (ULB), Brussels, Belgium.
authors: Olivier
authors: O
authors: Michel
authors: Tricia D
authors: TD
authors: LeVan
authors: Debbie
authors: D
authors: Stern
authors: Mieke
authors: M
authors: Dentener
authors: Jörgen
authors: J
authors: Thorn
authors: Daniele
authors: D
authors: Gnat
authors: M Lena
authors: ML
authors: Beijer
authors: Pascale
authors: P
authors: Cochaux
authors: Patrick G
authors: PG
authors: Holt
authors: Fernando D
authors: FD
authors: Martinez
authors: Ragnar
authors: R
authors: Rylander
mesh_terms: D000209:Acute-Phase Proteins; D000280:Administration, Inhalation; D000328:Adult; D000483:Alleles; D002097:C-Reactive Protein / Q000378:metabolism; D002352:Carrier Proteins / Q000097:blood; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007249:Inflammation / Q000139:chemically induced* / Q000235:genetics*; D007958:Leukocyte Count; D015810:Linkage Disequilibrium; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008562:Membrane Glycoproteins / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011956:Receptors, Cell Surface / Q000235:genetics*; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D000099231:Lipopolysaccharide-Binding Protein
chemical_list: D000209:Acute-Phase Proteins; D002097:C-Reactive Protein; D002352:Carrier Proteins; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D000099231:Lipopolysaccharide-Binding Protein; C495345:TLR4 protein, human