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


OBJECTIVE
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.


CONCLUSIONS
The single-nucleotide polymorphisms at position +896 or +1196 in the TLR-4 gene is associated with systemic inflammatory hyporesponsiveness to inhaled lipopolysaccharide.
Michel
Olivier
O
Clinic of Allergology and Respiratory Diseases, CHU Saint-Pierre (ULB), Brussels, Belgium.
LeVan
Tricia D
TD
Stern
Debbie
D
Dentener
Mieke
M
Thorn
Jörgen
J
Gnat
Daniele
D
Beijer
M Lena
ML
Cochaux
Pascale
P
Holt
Patrick G
PG
Martinez
Fernando D
FD
Rylander
Ragnar
R
D000209:Acute-Phase Proteins; D000280:Administration, Inhalation; D000328:Adult; D000483:Alleles; D002097:C-Reactive Protein / Q000378:metabolism; D002352:Carrier Proteins / Q000097:blood; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007249:Inflammation / Q000139:chemically induced* / Q000235:genetics*; D007958:Leukocyte Count; D015810:Linkage Disequilibrium; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008562:Membrane Glycoproteins / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011956:Receptors, Cell Surface / Q000235:genetics*; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D000099231:Lipopolysaccharide-Binding Protein
D000209:Acute-Phase Proteins; D002097:C-Reactive Protein; D002352:Carrier Proteins; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D000099231:Lipopolysaccharide-Binding Protein; C495345:TLR4 protein, human