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- DOI: 10.1111/all.12504
- PMID: 25102764
- UKPMCID: 25102764
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Polymorphisms of endotoxin pathway and endotoxin exposure: in-vitro IgE synthesis and replication in a birth cohort.
Sahiner, Umit M; Jusufagic, Aida Semic-; Curtin, John A; Birben, Esra; Belgrave, Danielle; Sackesen, Cansin; Simpson, Angela; Yavuz, Tolga S; Akdis, Cezmi A; Custovic, Adnan; Kalayci, Omer
Allergy. 2014;.
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Full-text held externally
- DOI: 10.1111/all.12504
- PMID: 25102764
- UKPMCID: 25102764
Abstract
BACKGROUND: Genetic variants in endotoxin signaling pathway are important in modulating the effect of environmental endotoxin on asthma and atopic phenotypes. Our objective was to determine the single nucleotide polymorphisms (SNPs) in the endotoxin signaling pathway that may influence in-vitro IgE synthesis and investigate the relationship between these variants and endotoxin exposure in relation to the development of asthma and atopy in a birth cohort. METHODS: Peripheral blood mononuclear cells from 45 asthmatic children were stimulated with 2 and 200 ng/ml lipopolysaccharide in-vitro and IgE was measured in the culture supernatants. Children were genotyped for 121 SNPs from 30 genes in the endotoxin signaling pathway. Variants with a dose-response IgE production in relation to LPS were selected for replication in a population-based birth cohort, in which we investigated the interaction between these SNPs and endotoxin exposure in relation to airway hyperresponsiveness, wheeze and atopic sensitization. RESULTS: 21 SNPs in nine genes (CD14, TLR4, IRF3, TRAF-6, TIRAP, TRIF, IKK-1, ST2, SOCS1) were found to modulate the effect of endotoxin on in-vitro IgE synthesis, with 6 displaying high linkage disequilibrium. Of the remaining 15 SNPs, for 7 we found significant relationships between genotype and endotoxin exposure in the genetic association study in relation to symptomatic airway hyperresponsiveness (CD14-rs2915863 and rs2569191, TRIF-rs4807000), current wheeze (ST-2-rs17639215, IKK-1-rs2230804 and TRIF-rs4807000) and atopy (CD14-2915863 and rs2569192, TRAF-6-rs5030411 and IKK-1-rs2230804). CONCLUSIONS: Variants in the endotoxin signaling pathway are important determinants of asthma and atopy. The genotype effect is a function of the environmental endotoxin exposure. This article is protected by copyright. All rights reserved.
Keyword(s)
Asthma; Atopy; Endotoxin; Environment; Gene; IgE; Polymorphism; wheezing