Association of IL33-IL-1 receptor-like 1 (IL1RL1) pathway polymorphisms with wheezing phenotypes and asthma in childhood.

Abstract

BACKGROUND:

Genome-wide association studies identified IL33 and IL-1 receptor-like 1 (IL1RL1)/IL18R1 as asthma susceptibility loci. IL33 and IL1RL1 constitute a single ligand-receptor pathway.

OBJECTIVE:

In 2 birth cohorts, the Prevalence and Incidence of Asthma and Mite Allergy (PIAMA) study and Avon Longitudinal Study of Parents and Children (ALSPAC), we analyzed associations of longitudinal wheezing phenotypes and asthma with single nucleotide polymorphisms (SNPs) of 8 genes encoding IL-33, IL1RL1, its coreceptor IL1RAcP, its adaptors myeloid differentiation primary response gene 88 (MyD88) and Toll-IL-11 receptor domain containing adaptor protein (TIRAP), and the downstream IL-1 receptor-associated kinase 1, IL-1 receptor-associated kinase 4, and TNF receptor-associated factor 6 (TRAF6). Furthermore, we investigated whether SNPs in this pathway show replicable evidence of gene-gene interaction.

METHODS:

Ninety-four SNPs were investigated in 2007 children in the PIAMA study and 7247 children in ALSPAC. Associations with wheezing phenotypes and asthma at 8 years of age were analyzed in each cohort and subsequently meta-analyzed. Gene-gene interactions were assessed through model-based multifactor dimensionality reduction in the PIAMA study, and gene-gene interactions of 10 SNP pairs were further evaluated.

RESULTS:

Intermediate-onset wheeze was associated with SNPs in several genes in the IL33-IL1RL1 pathway after applying multiple testing correction in the meta-analysis: 2 IL33 SNPs (rs4742170 and rs7037276), 1 IL-1 receptor accessory protein (IL1RAP) SNP (rs10513854), and 1 TRAF6 SNP (rs5030411). Late-onset wheeze was associated with 2 IL1RL1 SNPs (rs10208293 and rs13424006), and persistent wheeze was associated with 1 IL33 SNP (rs1342326) and 1 IL1RAP SNP (rs9290936). IL33 and IL1RL1 SNPs were nominally associated with asthma. Three SNP pairs showed interaction for asthma in the PIAMA study but not in ALSPAC.

CONCLUSIONS:

IL33-IL1RL1 pathway polymorphisms are associated with asthma and specific wheezing phenotypes; that is, most SNPs are associated with intermediate-onset wheeze, a phenotype closely associated with sensitization. We speculate that IL33-IL1RL1 pathway polymorphisms affect development of wheeze and subsequent asthma through sensitization in early childhood.

• Authors: Olga E Savenije, Jestinah M Mahachie John, Raquel Granell, Marjan Kerkhof, F Nicole Dijk, Johan C de Jongste, Henriëtte A Smit, Bert Brunekreef, Dirkje S Postma, Kristel Van Steen, John Henderson, Gerard H Koppelman
• Journal: The Journal of allergy and clinical immunology (J Allergy Clin Immunol) Vol. 134 Issue 1 Pg. 170-7 (Jul 2014) ISSN: 1097-6825 [Electronic] United States
• PMID: 24568840 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

Chemical References

• IL1RAP protein, human
• IL1RL1 protein, human
• IL33 protein, human
• Interleukin-1 Receptor Accessory Protein
• Interleukin-1 Receptor-Like 1 Protein
• Interleukin-33
• Interleukins
• MYD88 protein, human
• Membrane Glycoproteins
• Myeloid Differentiation Factor 88
• Receptors, Cell Surface
• Receptors, Interleukin-1
• TIRAP protein, human

Topics

• Asthma (genetics, immunology, pathology)
• Child
• Child, Preschool
• Cohort Studies
• Epistasis, Genetic
• Female
• Genetic Predisposition to Disease
• Humans
• Infant
• Infant, Newborn
• Interleukin-1 Receptor Accessory Protein (genetics, immunology)
• Interleukin-1 Receptor-Like 1 Protein
• Interleukin-33
• Interleukins (genetics, immunology)
• Male
• Membrane Glycoproteins (genetics, immunology)
• Myeloid Differentiation Factor 88 (genetics, immunology)
• Polymorphism, Single Nucleotide
• Receptors, Cell Surface (genetics, immunology)
• Receptors, Interleukin-1 (genetics, immunology)
• Respiratory Sounds (immunology, physiopathology)
• Signal Transduction