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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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Genetic interactions between TOLLIP, TLR4, and IRAK1.Graphical display of evidence observed in MDR analysis of interaction among SNPs in TOLLIP (rs4963060), TLR4 (rs6478317) and IRAK1 (rs1059703). For each cell the left bar (empty) represents the number of children with PT-IgG in the highest 33rd percentile (total: 164) and the right bar (dark) the number of children with PT-IgG in the lowest 33rd percentile (total: 153) for the specific combination of 2 (fig 2A) or 3 genotypes (fig 2B). When the ratio is >164/153 the cell indicates a higher chance on a titer in the highest 33rd percentile (dark background), and when the ratio is <164/153 the cell indicates a higher chance on a titer in the lowest 33rd percentile (light background). 0, 1, and 2 represent the number of minor alleles.
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pone-0003665-g002: Genetic interactions between TOLLIP, TLR4, and IRAK1.Graphical display of evidence observed in MDR analysis of interaction among SNPs in TOLLIP (rs4963060), TLR4 (rs6478317) and IRAK1 (rs1059703). For each cell the left bar (empty) represents the number of children with PT-IgG in the highest 33rd percentile (total: 164) and the right bar (dark) the number of children with PT-IgG in the lowest 33rd percentile (total: 153) for the specific combination of 2 (fig 2A) or 3 genotypes (fig 2B). When the ratio is >164/153 the cell indicates a higher chance on a titer in the highest 33rd percentile (dark background), and when the ratio is <164/153 the cell indicates a higher chance on a titer in the lowest 33rd percentile (light background). 0, 1, and 2 represent the number of minor alleles.

Mentions: MDR analyses revealed two significant genetic interactions of SNPs in TOLLIP (rs4963060), TLR4 (rs6478317; syn.: rs2737190) and IRAK1 (rs1059703) with cases in the highest 33rd percentile compared to controls in the lowest 33rd percentile of PT-IgG titers (Table 5, Fig. 2a and Fig. 2b).


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)

Genetic interactions between TOLLIP, TLR4, and IRAK1.Graphical display of evidence observed in MDR analysis of interaction among SNPs in TOLLIP (rs4963060), TLR4 (rs6478317) and IRAK1 (rs1059703). For each cell the left bar (empty) represents the number of children with PT-IgG in the highest 33rd percentile (total: 164) and the right bar (dark) the number of children with PT-IgG in the lowest 33rd percentile (total: 153) for the specific combination of 2 (fig 2A) or 3 genotypes (fig 2B). When the ratio is >164/153 the cell indicates a higher chance on a titer in the highest 33rd percentile (dark background), and when the ratio is <164/153 the cell indicates a higher chance on a titer in the lowest 33rd percentile (light background). 0, 1, and 2 represent the number of minor alleles.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2573957&req=5

pone-0003665-g002: Genetic interactions between TOLLIP, TLR4, and IRAK1.Graphical display of evidence observed in MDR analysis of interaction among SNPs in TOLLIP (rs4963060), TLR4 (rs6478317) and IRAK1 (rs1059703). For each cell the left bar (empty) represents the number of children with PT-IgG in the highest 33rd percentile (total: 164) and the right bar (dark) the number of children with PT-IgG in the lowest 33rd percentile (total: 153) for the specific combination of 2 (fig 2A) or 3 genotypes (fig 2B). When the ratio is >164/153 the cell indicates a higher chance on a titer in the highest 33rd percentile (dark background), and when the ratio is <164/153 the cell indicates a higher chance on a titer in the lowest 33rd percentile (light background). 0, 1, and 2 represent the number of minor alleles.
Mentions: MDR analyses revealed two significant genetic interactions of SNPs in TOLLIP (rs4963060), TLR4 (rs6478317; syn.: rs2737190) and IRAK1 (rs1059703) with cases in the highest 33rd percentile compared to controls in the lowest 33rd percentile of PT-IgG titers (Table 5, Fig. 2a and Fig. 2b).

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