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Association of interacting genes in the toll-like receptor signaling pathway and the antibody response to pertussis vaccination.

Kimman TG, Banus S, Reijmerink N, Reimerink J, Stelma FF, Koppelman GH, Thijs C, Postma DS, Kerkhof M - PLoS ONE (2008)

Bottom Line: 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.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).

View Article: PubMed Central - PubMed

Affiliation: Center for Infectious Disease Control, National Institute of Public Health and Environment, Bilthoven, The Netherlands. tg.kimman@rivm.nl

ABSTRACT

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.

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Summary of the TLR pathway in antigen-presenting cells and the main results of this paper.TLRs recognize molecular patterns associated with a broad range of pathogens including bacteria, fungi, protozoa and viruses. Vaccine components in WCV vaccine that may be recognized by TLR4 include LPS and PT. Following TLR4 activation, both the MyD88 and TICAM1 routes, leading to the expression of proinflammatory cytokines and type I IFNs respectively, may be activated. These promote the development of helper T cell responses providing T-cell help to B cells. TLR signaling in B cells may further promote the generation of antibody responses and the maintenance of serologic memory. TNFRSF4 is expressed on activated T cells. Adapted from BioCarta (http://www.biocarta.com/pathfiles/h_tollPathway.asp), KEGG (Kyoto Encyclopedia of Genes and Genomes) [50], and Metacore™ (http://www.genego.com/metacore.php).
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pone-0003665-g001: Summary of the TLR pathway in antigen-presenting cells and the main results of this paper.TLRs recognize molecular patterns associated with a broad range of pathogens including bacteria, fungi, protozoa and viruses. Vaccine components in WCV vaccine that may be recognized by TLR4 include LPS and PT. Following TLR4 activation, both the MyD88 and TICAM1 routes, leading to the expression of proinflammatory cytokines and type I IFNs respectively, may be activated. These promote the development of helper T cell responses providing T-cell help to B cells. TLR signaling in B cells may further promote the generation of antibody responses and the maintenance of serologic memory. TNFRSF4 is expressed on activated T cells. Adapted from BioCarta (http://www.biocarta.com/pathfiles/h_tollPathway.asp), KEGG (Kyoto Encyclopedia of Genes and Genomes) [50], and Metacore™ (http://www.genego.com/metacore.php).

Mentions: Based on the recent literature and assisted by the online pathway-visualization program Metacore™ (http://www.genego.com/metacore.php) we have made a selection of genes in the TLR signaling pathway that could be associated with pertussis vaccine-induced antibody responses (Fig. 1). Haplotype tagging SNPs were selected from the HapMap database (http://www.hapmap.org/) or from the Innate Immunity web site (http://www.innateimmunity.net/datahomology) depending on the largest number of SNPs with a minor allele frequency >0.1 available in each database. Because pertussis vaccines may modulate the balance between Th1 and Th2 immunity [22], we further screened the biomedical literature until October 2005 for SNPs within the candidate genes known to have functional impact on, or to be associated with Th2 diseases, notably asthma and atopy. SNPs were named according to the Human Genome Variation Society guidelines (http://www.hgvs.org/mutnomen/recs.html). Rs numbers have been derived from the NCBI database (http://www.ncbi.nlm.nih.gov/sites/entrez).


Association of interacting genes in the toll-like receptor signaling pathway and the antibody response to pertussis vaccination.

Kimman TG, Banus S, Reijmerink N, Reimerink J, Stelma FF, Koppelman GH, Thijs C, Postma DS, Kerkhof M - PLoS ONE (2008)

Summary of the TLR pathway in antigen-presenting cells and the main results of this paper.TLRs recognize molecular patterns associated with a broad range of pathogens including bacteria, fungi, protozoa and viruses. Vaccine components in WCV vaccine that may be recognized by TLR4 include LPS and PT. Following TLR4 activation, both the MyD88 and TICAM1 routes, leading to the expression of proinflammatory cytokines and type I IFNs respectively, may be activated. These promote the development of helper T cell responses providing T-cell help to B cells. TLR signaling in B cells may further promote the generation of antibody responses and the maintenance of serologic memory. TNFRSF4 is expressed on activated T cells. Adapted from BioCarta (http://www.biocarta.com/pathfiles/h_tollPathway.asp), KEGG (Kyoto Encyclopedia of Genes and Genomes) [50], and Metacore™ (http://www.genego.com/metacore.php).
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2573957&req=5

pone-0003665-g001: Summary of the TLR pathway in antigen-presenting cells and the main results of this paper.TLRs recognize molecular patterns associated with a broad range of pathogens including bacteria, fungi, protozoa and viruses. Vaccine components in WCV vaccine that may be recognized by TLR4 include LPS and PT. Following TLR4 activation, both the MyD88 and TICAM1 routes, leading to the expression of proinflammatory cytokines and type I IFNs respectively, may be activated. These promote the development of helper T cell responses providing T-cell help to B cells. TLR signaling in B cells may further promote the generation of antibody responses and the maintenance of serologic memory. TNFRSF4 is expressed on activated T cells. Adapted from BioCarta (http://www.biocarta.com/pathfiles/h_tollPathway.asp), KEGG (Kyoto Encyclopedia of Genes and Genomes) [50], and Metacore™ (http://www.genego.com/metacore.php).
Mentions: Based on the recent literature and assisted by the online pathway-visualization program Metacore™ (http://www.genego.com/metacore.php) we have made a selection of genes in the TLR signaling pathway that could be associated with pertussis vaccine-induced antibody responses (Fig. 1). Haplotype tagging SNPs were selected from the HapMap database (http://www.hapmap.org/) or from the Innate Immunity web site (http://www.innateimmunity.net/datahomology) depending on the largest number of SNPs with a minor allele frequency >0.1 available in each database. Because pertussis vaccines may modulate the balance between Th1 and Th2 immunity [22], we further screened the biomedical literature until October 2005 for SNPs within the candidate genes known to have functional impact on, or to be associated with Th2 diseases, notably asthma and atopy. SNPs were named according to the Human Genome Variation Society guidelines (http://www.hgvs.org/mutnomen/recs.html). Rs numbers have been derived from the NCBI database (http://www.ncbi.nlm.nih.gov/sites/entrez).

Bottom Line: 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.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).

View Article: PubMed Central - PubMed

Affiliation: Center for Infectious Disease Control, National Institute of Public Health and Environment, Bilthoven, The Netherlands. tg.kimman@rivm.nl

ABSTRACT

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.

Show MeSH
Related in: MedlinePlus