Association of Interacting Genes in the Toll-Like Receptor Signaling Pathway and the Antibody Response to Pertussis Vaccination

BACKGROUND: Activation of the Toll-like receptor (TLR) signaling pathway through TLR4 may be important in the induction of protective immunity against Bordetella pertussis with TLR4-mediated activation of dendritic and B cells, induction of cytokine expression, and reversal of tolerance as crucial steps. We examined whether single nucleotide polymorphisms (SNPs) in genes of the TLR4 pathway and their interaction are associated with the response to whole-cell vaccine (WCV) pertussis vaccination in 490 one-year-old children. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed associations of 75 haplotype-tagging SNPs in genes in the TLR4 signaling pathway with pertussis toxin (PT)-IgG titers. We found significant associations between the PT-IgG titer and SNPs in CD14, TLR4, TOLLIP, TIRAP, IRAK3, IRAK4, TICAM1, and TNFRSF4 in one or more of the analyses. The strongest evidence for association was found for two SNPs (rs5744034 and rs5743894) in TOLLIP that were almost completely in linkage disequilibrium, provided statistically significant associations in all tests with the lowest p-values, and displayed a dominant mode of inheritance. However, none of these single gene associations would withstand correction for multiple testing. In addition, Multifactor Dimensionality Reduction Analysis, an approach that does not need correction for multiple testing, showed significant and strong two and three locus interactions between SNPs in TOLLIP (rs4963060), TLR4 (rs6478317) and IRAK1 (rs1059703). CONCLUSIONS/SIGNIFICANCE: We have identified significant interactions between genes in the TLR pathway in the induction of vaccine-induced immunity. These interactions underline that these genes are functionally related and together form a true biological relationship in a protein-protein interaction network. Practically all our findings may be explained by genetic variation in directly or indirectly interacting proteins at the extra- and intracytoplasmic sites of the cell membrane of antigen-presenting cells, B cells, or both. Fine tuning of interacting proteins in the TLR pathway appears important for the induction of an optimal vaccine response

A Search for missing pieces of the puzzle; the development of asthma and atopy

Het doel van het in dit proefschrift beschreven onderzoek is het vaststellen welke genen, omgevingsfactoren, en welke interacties tussen genen onderling en tussen genen en omgevingsfactoren een rol spelen bij de ontwikkeling van astma en atopie. Dit is onderzocht in diverse populaties; o.a. in astma families, astma trios en in de Allergenic studie. Hoofdstuk 1 geeft een overzicht van de huidige kennis over gen-gen en gen-omgeving interactie bij de ontwikkeling van longziekten bij kinderen. In hoofdstuk 2 tot en met 4 hebben wij kandidaatgenen onderzocht waarvan het aannemelijk is dat zij een rol spelen bij de ontwikkeling van astma en atopie. In Hoofdstuk 5 en 6 onderzochten wij verschillende eiwitten van de Toll like receptor (TLR) route. Deze eiwitten spelen een belangrijke rol in de aangeboren afweer. Wij tonen aan dat binnen deze route complexe gen-gen en gen-omgevingsinteracties een rol spelen bij de ontwikkeling van astma en atopie. Hoofdstuk 7 beschrijft interactie tussen ADAM33, het eerste ontdekte astmagen en roken. In hoofdstuk 8 beschrijven wij een studie naar de functionele effecten van het promoter polymorfisme rs2569190 (CD14/-159). De boven beschreven studies laten zien dat verschillende genen, omgevingsfactoren en complexe gen-gen en gen-omgevingsfactoren een rol spelen bij de ontwikkeling van astma en atopie. Onderzoek zoals beschreven in dit proefschrift zal helpen de immense astma en atopie puzzel op te lossen. Het vaststellen van de verschillende genetische- en omgevingsfactoren zal ervoor zorgen dat risicogroepen kunnen worden opgespoord en dat bijpassende levensstijl adviezen en therapeutische behandelingen aan deze groepen kunnen worden gegeven.

Host-microbial interactions in childhood atopy:Toll-like receptor 4 (TLR4), CD14, and fecal Escherichia coli

Background: Perturbations in the gut microbiota have been linked to atopic diseases. However, the development of atopic diseases depends not only on environmental factors (like microbial stimulation) but also on genetic factors. It is likely that particularly gene-environmental interactions in early life determine the development of atopy. Objective We examine the interaction between detection of fecal Escherichia coli and genetic variations in the CD14 and Toll-like receptor 4 (TLR4) genes in relation to atopic manifestations. Methods: Within the Child, Parent and Health: Lifestyle and Genetic Constitution (KOALA) Birth Cohort Study, fecal samples of 957 one-month-old infants were collected and quantitatively screened for E coli. Fourteen haplotype-tagging polymorphisms in the genes TLR4 and CD14 were genotyped in 681 of the 957 children. Atopic outcomes were parentally reported eczema in the first 2 years of life and clinically diagnosed eczema and allergic sensitization at age 2 years. Multiple logistic regression was used to evaluate a multiplicative model of interaction. Results: Most of the single nucleotide polymorphisms (SNPs) showed no significant interaction with E coli exposure for both eczema and allergic sensitization. A borderline significant multiplicative interaction was found between E coli and the rs2569190 (CD14/-159) SNP regarding allergic sensitization. Furthermore, a statistically significant multiplicative interaction was found for the TLR4 SNP rs10759932 (P for interaction = .001). E coli colonization was associated with a decreased risk of sensitization only in children with the rs10759932 TT genotype (adjusted odds ratio, 0.31; 95% CI, 0.14-0.68) and not in children with the minor C allele. This interaction remained statistically significant after controlling for multiple testing. Conclusion: The current study is the first to address the potential effect-modifying role of genetic variations in the relationship between the intestinal microbiota and allergy development. (J Allergy Clin Immunol 2010;125:231-6.