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 Martinez, Ragnar Rylander

Research output: Contribution to journalArticle

117 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 - Nov 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; Rylander, Ragnar.

In: Journal of Allergy and Clinical Immunology, Vol. 112, No. 5, 11.2003, 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, F & 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 ; 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

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.

AB - 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.

KW - C-reactive protein

KW - Endotoxin

KW - Inflammation

KW - Leukocytosis

KW - Lipopolysaccharide

KW - Toll-like receptor-4

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