Association ofIL33–IL-1 receptor–like 1 (IL1RL1) pathway polymorphisms with wheezing phenotypes and asthma in childhood

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Genome-wide association studies identifiedIL33and IL-1 receptor–like 1 (IL1RL1)/IL18R1as asthma susceptibility loci.IL33andIL1RL1constitute a single ligand-receptor pathway.


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.


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.


Intermediate-onset wheeze was associated with SNPs in several genes in theIL33-IL1RL1pathway after applying multiple testing correction in the meta-analysis: 2IL33SNPs (rs4742170 and rs7037276), 1 IL-1 receptor accessory protein(IL1RAP)SNP (rs10513854), and 1TRAF6SNP (rs5030411). Late-onset wheeze was associated with 2IL1RL1SNPs (rs10208293 and rs13424006), and persistent wheeze was associated with 1IL33SNP (rs1342326) and 1IL1RAPSNP (rs9290936).IL33andIL1RL1SNPs were nominally associated with asthma. Three SNP pairs showed interaction for asthma in the PIAMA study but not in ALSPAC.


IL33-IL1RL1pathway 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 thatIL33-IL1RL1pathway polymorphisms affect development of wheeze and subsequent asthma through sensitization in early childhood.

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