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

Research output: Contribution to journalArticle

115 Citations (Scopus)

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 - Jan 1 2003

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Toll-Like Receptor 4
Lipopolysaccharides
Genes
Homozygote
C-Reactive Protein
Inhalation
Single Nucleotide Polymorphism
Alleles
Linkage Disequilibrium
Leukocyte Count
Genetic Promoter Regions
Protein Binding
Healthy Volunteers

Keywords

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

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Systemic responsiveness to lipopolysaccharide and polymorphisms in the toll-like receptor 4 gene in human beings. / Michel, Olivier; LeVan, Tricia D; Stern, Debbie; Dentener, Mieke; Thorn, Jörgen; Gnat, Daniele; Beijer, M. Lena; Cochaux, Pascale; Holt, Patrick G.; Martinez, Fernando D.; Rylander, Ragnar.

In: Journal of Allergy and Clinical Immunology, Vol. 112, No. 5, 01.01.2003, p. 923-929.

Research output: Contribution to journalArticle

Michel, O, LeVan, TD, Stern, D, Dentener, M, Thorn, J, Gnat, D, Beijer, ML, Cochaux, P, Holt, PG, Martinez, FD & 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, vol. 112, no. 5, pp. 923-929. https://doi.org/10.1016/j.jaci.2003.05.001
Michel, Olivier ; LeVan, Tricia D ; Stern, Debbie ; Dentener, Mieke ; Thorn, Jörgen ; Gnat, Daniele ; Beijer, M. Lena ; Cochaux, Pascale ; Holt, Patrick G. ; Martinez, Fernando D. ; Rylander, Ragnar. / Systemic responsiveness to lipopolysaccharide and polymorphisms in the toll-like receptor 4 gene in human beings. In: Journal of Allergy and Clinical Immunology. 2003 ; Vol. 112, No. 5. pp. 923-929.
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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.",
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AU - Michel, Olivier

AU - LeVan, Tricia D

AU - Stern, Debbie

AU - Dentener, Mieke

AU - Thorn, Jörgen

AU - Gnat, Daniele

AU - Beijer, M. Lena

AU - Cochaux, Pascale

AU - Holt, Patrick G.

AU - Martinez, Fernando D.

AU - Rylander, Ragnar

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N2 - 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.

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