title: Polymorphisms of endotoxin pathway and endotoxin exposure: in vitro IgE synthesis and replication in a birth cohort.
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.
authors.affiliation: Pediatric Allergy and Asthma Unit, Hacettepe University School of Medicine, Ankara, Turkey.
authors.forename: U M
authors.initials: UM
authors.lastname: Sahiner
authors.forename: A
authors.initials: A
authors.lastname: Semic-Jusufagic
authors.forename: J A
authors.initials: JA
authors.lastname: Curtin
authors.forename: E
authors.initials: E
authors.lastname: Birben
authors.forename: D
authors.initials: D
authors.lastname: Belgrave
authors.forename: C
authors.initials: C
authors.lastname: Sackesen
authors.forename: A
authors.initials: A
authors.lastname: Simpson
authors.forename: T S
authors.initials: TS
authors.lastname: Yavuz
authors.forename: C A
authors.initials: CA
authors.lastname: Akdis
authors.forename: A
authors.initials: A
authors.lastname: Custovic
authors.forename: O
authors.initials: O
authors.lastname: Kalayci
mesh_terms: D000293:Adolescent; D000483:Alleles; D001249:Asthma / Q000175:diagnosis / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D002648:Child; D015331:Cohort Studies; D004731:Endotoxins / Q000276:immunology* / Q000378:metabolism; D004781:Environmental Exposure; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D006969:Hypersensitivity, Immediate / Q000175:diagnosis / Q000235:genetics / Q000276:immunology; D007073:Immunoglobulin E / Q000096:biosynthesis* / Q000276:immunology*; D066298:In Vitro Techniques; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D015398:Signal Transduction
chemical_list: D004731:Endotoxins; D007073:Immunoglobulin E
keywords: IgE; asthma; atopy; endotoxin; gene