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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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Influence of TOLLIP and TRL4 and their interaction on log PT-IgG titers.Influence of TOLLIP (rs4963060) and TLR4 (rs6478317) interaction on log PT-IgG titers following pertussis vaccination in a dominant model of inheritance. The presence of one or two minor alleles of one of these SNPs, but not the presence of one or two minor alleles of both SNPs, was associated with a lower PT-IgG titer. 0, 1, and 2 represent the number of minor alleles. * Significantly different from the group homozygous for the wild-type alleles (p = 0.04). P interaction term = 0.01. Vertical bars indicate standard errors.
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pone-0003665-g003: Influence of TOLLIP and TRL4 and their interaction on log PT-IgG titers.Influence of TOLLIP (rs4963060) and TLR4 (rs6478317) interaction on log PT-IgG titers following pertussis vaccination in a dominant model of inheritance. The presence of one or two minor alleles of one of these SNPs, but not the presence of one or two minor alleles of both SNPs, was associated with a lower PT-IgG titer. 0, 1, and 2 represent the number of minor alleles. * Significantly different from the group homozygous for the wild-type alleles (p = 0.04). P interaction term = 0.01. Vertical bars indicate standard errors.

Mentions: First, a combination of a TOLLIP SNP (rs4963060) and a TLR4 SNP (rs6478317) had a strong synergistic effect on PT-IgG titers (p = 0.01; average testing balanced accuracy 61%). The interaction was confirmed by linear regression analysis for the level of PT-IgG as the outcome (p-value for interaction term = 0.01), and by logistic regression analysis for the highest 33rd percentile compared to the lowest 33rd percentile (p-value for interaction term = 0.0005). Figure 2 shows which combinations of genotypes have relatively high levels of PT-IgG, i.e. dark shaded cells with a high ratio of cases (left bars) and controls (right bars). Especially children with wild type genotypes of both TOLLIP (rs4963060) and TLR4 (rs6478317) had a high chance of PT-IgG in the highest 33rd percentile (Fig. 2A, Fig. 3). The strong and significant interaction between the TOLLIP (rs4963060) and TLR4 (rs6478317) SNPs was further indicated by a positive information gain based on measures of entropy [28], [29]. That is, information about case-control status is gained above that provided by the SNPs individually by combining the two SNPs (data not shown).


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)

Influence of TOLLIP and TRL4 and their interaction on log PT-IgG titers.Influence of TOLLIP (rs4963060) and TLR4 (rs6478317) interaction on log PT-IgG titers following pertussis vaccination in a dominant model of inheritance. The presence of one or two minor alleles of one of these SNPs, but not the presence of one or two minor alleles of both SNPs, was associated with a lower PT-IgG titer. 0, 1, and 2 represent the number of minor alleles. * Significantly different from the group homozygous for the wild-type alleles (p = 0.04). P interaction term = 0.01. Vertical bars indicate standard errors.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0003665-g003: Influence of TOLLIP and TRL4 and their interaction on log PT-IgG titers.Influence of TOLLIP (rs4963060) and TLR4 (rs6478317) interaction on log PT-IgG titers following pertussis vaccination in a dominant model of inheritance. The presence of one or two minor alleles of one of these SNPs, but not the presence of one or two minor alleles of both SNPs, was associated with a lower PT-IgG titer. 0, 1, and 2 represent the number of minor alleles. * Significantly different from the group homozygous for the wild-type alleles (p = 0.04). P interaction term = 0.01. Vertical bars indicate standard errors.
Mentions: First, a combination of a TOLLIP SNP (rs4963060) and a TLR4 SNP (rs6478317) had a strong synergistic effect on PT-IgG titers (p = 0.01; average testing balanced accuracy 61%). The interaction was confirmed by linear regression analysis for the level of PT-IgG as the outcome (p-value for interaction term = 0.01), and by logistic regression analysis for the highest 33rd percentile compared to the lowest 33rd percentile (p-value for interaction term = 0.0005). Figure 2 shows which combinations of genotypes have relatively high levels of PT-IgG, i.e. dark shaded cells with a high ratio of cases (left bars) and controls (right bars). Especially children with wild type genotypes of both TOLLIP (rs4963060) and TLR4 (rs6478317) had a high chance of PT-IgG in the highest 33rd percentile (Fig. 2A, Fig. 3). The strong and significant interaction between the TOLLIP (rs4963060) and TLR4 (rs6478317) SNPs was further indicated by a positive information gain based on measures of entropy [28], [29]. That is, information about case-control status is gained above that provided by the SNPs individually by combining the two SNPs (data not shown).

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