Document Detail


Toll-like receptor heterodimer variants protect from childhood asthma.
MedLine Citation:
PMID:  18547625     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: Early exposure to microbes reduces the risk for asthma. Toll-like receptors (TLRs) represent a major group of receptors for the specific recognition of pathogen-associated molecular patterns of microbes capable of activating innate and adaptive immunity. OBJECTIVE: Because TLRs can influence key events in the induction and perpetuation of asthma and atopy, we sought to determine whether genetic alterations in TLR genes affect asthma risk. METHODS: We systematically evaluated putatively functional genetic variants in all 10 human TLR genes for their association with different asthma phenotypes in a case-control study (n = 1872) by using matrix-assisted laser desorption/ionization time-of-flight genotyping. For polymorphisms showing association with atopic asthma, effects on gene and protein expression were studied by means of RT-PCR and flow cytometry ex vivo. T-cell cytokine production was evaluated by means of ELISA after stimulation of the respective TLRs with specific ligands. RESULTS: Protective effects on atopic asthma were identified for single nucleotide polymorphisms in TLR1 (odds ratio [OR], 0.54; 95% CI, 0.37-0.81; P = .002), TLR6 (OR, 0.54; 95% CI, 0.37-0.79; P = .003), and TLR10 (OR, 0.58; 95% CI, 0.39-0.86; P = .006), all capable of forming heterodimers with TLR2. Effects remained significant after correction for multiple comparisons. PBMCs of minor allele carriers showed increased levels of the respective TLR mRNA and proteins, augmented inflammatory responses, increased T(H)1 cytokine expression, and reduced T(H)2-associated IL-4 production after specific stimulation. CONCLUSION: These results suggest that functional relevant TLR1 and TLR6 variants are directly involved in asthma development.
Authors:
Michael S D Kormann; Martin Depner; Dominik Hartl; Norman Klopp; Thomas Illig; Jerzy Adamski; Christian Vogelberg; Stephan K Weiland; Erika von Mutius; Michael Kabesch
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2008-06-10
Journal Detail:
Title:  The Journal of allergy and clinical immunology     Volume:  122     ISSN:  1097-6825     ISO Abbreviation:  J. Allergy Clin. Immunol.     Publication Date:  2008 Jul 
Date Detail:
Created Date:  2008-07-08     Completed Date:  2008-07-29     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  1275002     Medline TA:  J Allergy Clin Immunol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  86-92, 92.e1-8     Citation Subset:  AIM; IM    
Affiliation:
University Children's Hospital, Ludwig-Maximilians-Universität, Munich, Germany.
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MeSH Terms
Descriptor/Qualifier:
Alleles
Asthma / genetics*,  immunology
Case-Control Studies
Child
Cytokines / biosynthesis,  immunology
Dimerization
Gene Frequency
Genetic Predisposition to Disease*
Genotype
Humans
Polymorphism, Single Nucleotide*
Toll-Like Receptor 1 / genetics,  immunology
Toll-Like Receptor 6 / genetics,  immunology
Toll-Like Receptors / genetics*,  immunology
Chemical
Reg. No./Substance:
0/Cytokines; 0/TLR6 protein, human; 0/Toll-Like Receptor 1; 0/Toll-Like Receptor 6; 0/Toll-Like Receptors

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