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Polymorphisms of endotoxin pathway and endotoxin exposure: in vitro IgE synthesis and replication in a birth cohort.

Sahiner, U M; Semic-Jusufagic, A; Curtin, J A; Birben, E; Belgrave, D; Sackesen, C; Simpson, A; Yavuz, T S; Akdis, C A; Custovic, A; Kalayci, O

Allergy. 2014;69(12):1648-58.

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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 to 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 children with asthma 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 lipopolysaccharide (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 hyper-responsiveness, wheeze, and atopic sensitization. RESULTS: Twenty-one SNPs in nine genes (CD14, TLR4, IRF3, TRAF-6, TIRAP, TRIF, IKK-1, ST-2, SOCS1) were found to modulate the effect of endotoxin on in vitro IgE synthesis, with six displaying high linkage disequilibrium. Of the remaining 15 SNPs, for seven we found significant relationships between genotype and endotoxin exposure in the genetic association study in relation to symptomatic airway hyper-responsiveness (CD14-rs2915863 and rs2569191, TRIF-rs4807000), current wheeze (ST-2-rs17639215, IKK-1-rs2230804, and TRIF-rs4807000), and atopy (CD14-rs2915863 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.

Keyword(s)

IgE; asthma; atopy; endotoxin; gene

Bibliographic metadata

Type of resource:
Content type:
Publication type:
Published date:
Journal title:
Abbreviated journal title:
ISSN:
Place of publication:
Denmark
Volume:
69
Issue:
12
Pagination:
1648-58
Digital Object Identifier:
10.1111/all.12504
Pubmed Identifier:
25102764
Access state:
Active

Institutional metadata

University researcher(s):

Record metadata

Manchester eScholar ID:
uk-ac-man-scw:255611
Created by:
Sadler, Alexandra
Created:
29th January, 2015, 10:15:27
Last modified by:
Sadler, Alexandra
Last modified:
29th January, 2015, 10:15:27

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