TLR‐related pathway analysis: novel gene–gene interactions in the development of asthma and atopy

Abstract

To cite this article: Reijmerink NE, Bottema RWB, Kerkhof M, Gerritsen J, Stelma FF, Thijs C, van Schayck CP, Smit HA, Brunekreef B, Koppelman GH, Postma DS. TLR‐related pathway analysis: novel gene–gene interactions in the development of asthma and atopy. Allergy 2010; 65: 199–207. Abstract 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. Conclusion: 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.