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.


RESULTS
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
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.
Kimman
Tjeerd G
TG
Center for Infectious Disease Control, National Institute of Public Health and Environment, Bilthoven, The Netherlands. tg.kimman@rivm.nl
Banus
Sander
S
Reijmerink
Naomi
N
Reimerink
Johan
J
Stelma
Foekje F
FF
Koppelman
Gerard H
GH
Thijs
Carel
C
Postma
Dirkje S
DS
Kerkhof
Marjan
M
D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000276:immunology; D000907:Antibodies, Bacterial / Q000096:biosynthesis* / Q000276:immunology; D015331:Cohort Studies; D005260:Female; D053263:Gene Regulatory Networks; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D007074:Immunoglobulin G / Q000096:biosynthesis* / Q000276:immunology; D007223:Infant; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics / Q000276:immunology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology; D015810:Linkage Disequilibrium; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology; D010567:Pertussis Vaccine / Q000276:immunology*; D020641:Polymorphism, Single Nucleotide; D017472:Receptors, Interleukin-1 / Q000235:genetics / Q000276:immunology; D053262:Receptors, OX40 / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology; D051193:Toll-Like Receptors / Q000235:genetics / Q000276:immunology*; D014611:Vaccination
D033942:Adaptor Proteins, Vesicular Transport; D000907:Antibodies, Bacterial; D007074:Immunoglobulin G; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D010567:Pertussis Vaccine; D017472:Receptors, Interleukin-1; D053262:Receptors, OX40; C470409:TICAM1 protein, human; C434984:TIRAP protein, human; C495345:TLR4 protein, human; C505716:TNFRSF4 protein, human; C410602:TOLLIP protein, human; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; C507768:IRAK1 protein, human; C507771:IRAK3 protein, human; C507773:IRAK4 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases