title: Toll-like receptors and microbial exposure: gene-gene and gene-environment interaction in the development of atopy.
abstract: Environmental and genetic factors contribute to atopy development. High microbial exposure may confer a protective effect on atopy. Toll-like receptors (TLRs) bind microbial products and are important in activating the immune system. To assess whether interactions between microbial exposures and genes encoding TLRs (and related genes) result in atopy, genes, environmental factors and gene-environment interactions of 66 single-nucleotide polymorphisms (SNPs) of 12 genes (TLR 1-6, 9 and 10, CD14, MD2, lipopolysaccharide-binding protein (LBP) and Dectin-1), and six proxy parameters of microbial exposure (sibship size, pets (three different parameters), day-care and intrauterine and childhood tobacco smoke exposure) were analysed for association with atopic phenotypes in 3,062 Dutch children (the Allergenic study). The presence of two or more older siblings increased the risk of developing high total immunoglobulin (Ig)E levels at different ages. This risk increased further in children aged 1-2 yrs carrying the minor allele of TLR6 SNP rs1039559. Furthermore, novel two- and three-factor gene-gene and gene-environment interactions were found (e.g. between sibship size, day-care and LBP SNP rs2232596). Larger sibship size is associated with increased total IgE levels. Furthermore, complex two- and three-factor interactions exist between genes and the environment. The TLRs and related genes interact with proxy parameters of high microbial exposure in atopy development.
authors.affiliation: Department of Pulmonology, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: N E
authors.initials: NE
authors.lastname: Reijmerink
authors.forename: M
authors.initials: M
authors.lastname: Kerkhof
authors.forename: R W B
authors.initials: RW
authors.lastname: Bottema
authors.forename: J
authors.initials: J
authors.lastname: Gerritsen
authors.forename: F F
authors.initials: FF
authors.lastname: Stelma
authors.forename: C
authors.initials: C
authors.lastname: Thijs
authors.forename: C P
authors.initials: CP
authors.lastname: van Schayck
authors.forename: H A
authors.initials: HA
authors.lastname: Smit
authors.forename: B
authors.initials: B
authors.lastname: Brunekreef
authors.forename: D S
authors.initials: DS
authors.lastname: Postma
authors.forename: G H
authors.initials: GH
authors.lastname: Koppelman
mesh_terms: D016902:Air Pollution, Indoor / Q000706:statistics & numerical data; D001419:Bacteria / Q000276:immunology; D002648:Child; D002656:Child Day Care Centers / Q000706:statistics & numerical data; D002675:Child, Preschool; D004781:Environmental Exposure / Q000706:statistics & numerical data; D004843:Epistasis, Genetic / Q000235:genetics*; D005260:Female; D059647:Gene-Environment Interaction; D006801:Humans; D006967:Hypersensitivity / Q000453:epidemiology / Q000235:genetics* / Q000276:immunology; D007107:Immune System / Q000254:growth & development / Q000276:immunology / Q000382:microbiology; D007073:Immunoglobulin E / Q000097:blood / Q000276:immunology; D007223:Infant; D008297:Male; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012307:Risk Factors; D035781:Siblings; D051193:Toll-Like Receptors / Q000235:genetics* / Q000276:immunology
chemical_list: D051193:Toll-Like Receptors; D007073:Immunoglobulin E