TLR-related pathway analysis: novel gene-gene interactions in the development of asthma and atopy.
BACKGROUND
The toll-like receptor (TLR)-related pathway is important in host defence and may be crucial in the development of asthma and atopy. Numerous studies have shown associations of TLR-related pathway genes with asthma and atopy phenotypes. So far it has not been investigated whether gene-gene interactions in this pathway contribute to atopy and asthma development.


METHODS
One hundred and sixty-nine haplotype tagging single nucleotide polymorphisms (SNPs) of 29 genes (i.e. membrane and intracellular receptors, TLR4 or lipopolysaccharide-binding/facilitating proteins, adaptors, interleukin-1 receptor associated kinases, kinases, chaperone molecules, transcription factors and inhibitors) were analysed for single- and multilocus associations with atopy [total and specific immunglobulin E (IgE) at 1-2 and 6-8 years] and asthma (6-8 years). A total of 3062 Dutch children from the birth cohorts PIAMA, PREVASC and KOALA (Allergenic study) were investigated. Chi-squared test, logistic regression and the data mining approach multifactor dimensionality reduction method (MDR) were used in analysis.


RESULTS
Several genes in the TLR-related pathway were associated with atopy and/or asthma [e.g. IL1RL1, BPI, NOD1, NOD2 and MAP3K7IP1]. Multiple, single associations were found with the phenotypes under study. MDR analysis showed novel, significant gene-gene interactions in association with atopy and asthma phenotypes (e.g. IL1RL1 and TLR4 with sIgE to indoor allergens and IRAK1, NOD1 and MAP3K7IP1 with asthma). Interestingly, gene-gene interactions were identified with SNPs that did not have an effect on their own.


CONCLUSIONS
Our unbiased approach provided suggestive evidence for interaction between several TLR-related pathway genes important in atopy and/or asthma development and pointed to novel genes.
Reijmerink
N E
NE
Department of Pulmonology, University Medical Center Groningen, University of Groningen, the Netherlands.
Bottema
R W B
RW
Kerkhof
M
M
Gerritsen
J
J
Stelma
F F
FF
Thijs
C
C
van Schayck
C P
CP
Smit
H A
HA
Brunekreef
B
B
Koppelman
G H
GH
Postma
D S
DS
D001249:Asthma / Q000235:genetics* / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D005260:Female; D005838:Genotype; D006801:Humans; D006969:Hypersensitivity, Immediate / Q000235:genetics* / Q000276:immunology; D007073:Immunoglobulin E / Q000097:blood / Q000276:immunology; D007223:Infant; D008297:Male; D020641:Polymorphism, Single Nucleotide; D015398:Signal Transduction / Q000235:genetics* / Q000276:immunology; D051193:Toll-Like Receptors / Q000235:genetics* / Q000276:immunology
D051193:Toll-Like Receptors; D007073:Immunoglobulin E