Systemic responsiveness to lipopolysaccharide and polymorphisms in the toll-like receptor 4 gene in human beings

J Allergy Clin Immunol. 2003 Nov;112(5):923-9. doi: 10.1016/j.jaci.2003.05.001.


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.

Objectives: 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.

Conclusion: The single-nucleotide polymorphisms at position +896 or +1196 in the TLR-4 gene is associated with systemic inflammatory hyporesponsiveness to inhaled lipopolysaccharide.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acute-Phase Proteins*
  • Administration, Inhalation
  • Adult
  • Alleles
  • C-Reactive Protein / metabolism
  • Carrier Proteins / blood
  • Heterozygote
  • Homozygote
  • Humans
  • Inflammation / chemically induced*
  • Inflammation / genetics*
  • Leukocyte Count
  • Linkage Disequilibrium
  • Lipopolysaccharides* / administration & dosage
  • Membrane Glycoproteins / genetics*
  • Middle Aged
  • Polymorphism, Single Nucleotide*
  • Receptors, Cell Surface / genetics*
  • Toll-Like Receptor 4
  • Toll-Like Receptors


  • Acute-Phase Proteins
  • Carrier Proteins
  • Lipopolysaccharides
  • Membrane Glycoproteins
  • Receptors, Cell Surface
  • TLR4 protein, human
  • Toll-Like Receptor 4
  • Toll-Like Receptors
  • lipopolysaccharide-binding protein
  • C-Reactive Protein