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J Allergy Clin Immunol. 2003 Nov;112(5):923-9.

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

Author information

1
Clinic of Allergology and Respiratory Diseases, CHU Saint-Pierre (ULB), Brussels, Belgium.

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 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.

PMID:
14610481
DOI:
10.1016/j.jaci.2003.05.001
[Indexed for MEDLINE]

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