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

Olivier Michel, Tricia D. LeVan, Debbie Stern, Mieke Dentener, Jörgen Thorn, Daniele Gnat, M. Lena Beijer, Pascale Cochaux, Patrick G. Holt, Fernando D. Martinez, Ragnar Rylander

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117 Scopus citations

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. 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 μg 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.

Original languageEnglish (US)
Pages (from-to)923-929
Number of pages7
JournalJournal of Allergy and Clinical Immunology
Volume112
Issue number5
DOIs
StatePublished - Nov 2003

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Keywords

  • C-reactive protein
  • Endotoxin
  • Inflammation
  • Leukocytosis
  • Lipopolysaccharide
  • Toll-like receptor-4

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Michel, O., LeVan, T. D., Stern, D., Dentener, M., Thorn, J., Gnat, D., Beijer, M. L., Cochaux, P., Holt, P. G., Martinez, F. D., & Rylander, R. (2003). Systemic responsiveness to lipopolysaccharide and polymorphisms in the toll-like receptor 4 gene in human beings. Journal of Allergy and Clinical Immunology, 112(5), 923-929. https://doi.org/10.1016/j.jaci.2003.05.001