title: Polymorphisms in toll-like receptor 4 are not associated with asthma or atopy-related phenotypes.
abstract: 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.
authors.affiliation: Channing Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. benjamin.raby@channing.harvard.edu
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Raby
authors.forename: Walter T
authors.initials: WT
authors.lastname: Klimecki
authors.forename: Catherine
authors.initials: C
authors.lastname: Laprise
authors.forename: Yannick
authors.initials: Y
authors.lastname: Renaud
authors.forename: Janet
authors.initials: J
authors.lastname: Faith
authors.forename: Mathieu
authors.initials: M
authors.lastname: Lemire
authors.forename: Celia
authors.initials: C
authors.lastname: Greenwood
authors.forename: Katherine M
authors.initials: KM
authors.lastname: Weiland
authors.forename: Christoph
authors.initials: C
authors.lastname: Lange
authors.forename: Lyle J
authors.initials: LJ
authors.lastname: Palmer
authors.forename: Ross
authors.initials: R
authors.lastname: Lazarus
authors.forename: Donata
authors.initials: D
authors.lastname: Vercelli
authors.forename: David J
authors.initials: DJ
authors.lastname: Kwiatkowski
authors.forename: Edwin K
authors.initials: EK
authors.lastname: Silverman
authors.forename: Fernando D
authors.initials: FD
authors.lastname: Martinez
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Hudson
authors.forename: Scott T
authors.initials: ST
authors.lastname: Weiss
mesh_terms: 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
chemical_list: D029721:Drosophila Proteins; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors