Polymorphisms in toll-like receptor 4 are not associated with asthma or atopy-related phenotypes.
Toll-like receptor 4 (TLR4) is the principal receptor for bacterial endotoxin recognition, and functional variants in the gene confer endotoxin-hyporesponsiveness in humans. Furthermore, there is evidence that endotoxin exposure during early life is protective against the development of atopy and asthma, although this relationship remains poorly understood. It is therefore possible that genetic variation in the TLR4 locus contributes to asthma susceptibility. In this study we characterize the genetic diversity in the TLR4 locus and test for association between the common genetic variants and asthma-related phenotypes. In a cohort of 90 ethnically diverse subjects, we resequenced the TLR4 locus and identified a total of 29 single nucleotide polymorphisms. We assessed five common polymorphisms for evidence of association with asthma in two large family-based cohorts: a heterogeneous North American cohort (589 families), and a more homogenous population from northeastern Quebec, Canada (167 families). Using the transmission-disequilibrium test, we found no evidence of association for any of the polymorphisms tested, including two functional variants. Furthermore, we found no evidence for association between the TLR4 variants and four quantitative intermediate asthma- and atopy-related phenotypes. Based on these results, we found no evidence that genetic variation in TLR4 contributes to asthma susceptibility.
Raby
Benjamin A
BA
Channing Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. benjamin.raby@channing.harvard.edu
Klimecki
Walter T
WT
Laprise
Catherine
C
Renaud
Yannick
Y
Faith
Janet
J
Lemire
Mathieu
M
Greenwood
Celia
C
Weiland
Katherine M
KM
Lange
Christoph
C
Palmer
Lyle J
LJ
Lazarus
Ross
R
Vercelli
Donata
D
Kwiatkowski
David J
DJ
Silverman
Edwin K
EK
Martinez
Fernando D
FD
Hudson
Thomas J
TJ
Weiss
Scott T
ST
D001249:Asthma / Q000235:genetics*; D002874:Chromosome Mapping; D015331:Cohort Studies; D029721:Drosophila Proteins; D006239:Haplotypes; D006801:Humans; D006967:Hypersensitivity / Q000235:genetics*; D015810:Linkage Disequilibrium; D008562:Membrane Glycoproteins / Q000235:genetics*; D010641:Phenotype; D011110:Polymorphism, Genetic / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000235:genetics*; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
D029721:Drosophila Proteins; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors