title: 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.affiliation: University of Groningen, University Medical Center Groningen, Department of Epidemiology, GRIAC Research Institute, Groningen, The Netherlands; University of Groningen, University Medical Center Groningen, Department of Pediatrics, Beatrix Children's Hospital, GRIAC Research Institute, Groningen, The Netherlands.
authors.forename: Olga E
authors.initials: OE
authors.lastname: Savenije
authors.affiliation: Systems and Modeling Unit, Montefiore Institute, University of Liege, Liege, Belgium; Bioinformatics and Modeling, GIGA-R, University of Liege, Liege, Belgium.
authors.forename: Jestinah M
authors.initials: JM
authors.lastname: Mahachie John
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.
authors.forename: Raquel
authors.initials: R
authors.lastname: Granell
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Epidemiology, GRIAC Research Institute, Groningen, The Netherlands.
authors.forename: Marjan
authors.initials: M
authors.lastname: Kerkhof
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Pediatric Pulmonology and Pediatric Allergology, Beatrix Children's Hospital, GRIAC Research Institute, Groningen, The Netherlands.
authors.forename: F Nicole
authors.initials: FN
authors.lastname: Dijk
authors.affiliation: Department of Pediatrics/Respiratory Medicine, Erasmus University Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: Johan C
authors.initials: JC
authors.lastname: de Jongste
authors.affiliation: Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Henriëtte A
authors.initials: HA
authors.lastname: Smit
authors.affiliation: Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands; Institute for Risk Assessment Sciences, Utrecht University, Utrecht, The Netherlands.
authors.forename: Bert
authors.initials: B
authors.lastname: Brunekreef
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Pulmonology, GRIAC Research Institute, Groningen, The Netherlands.
authors.forename: Dirkje S
authors.initials: DS
authors.lastname: Postma
authors.affiliation: Systems and Modeling Unit, Montefiore Institute, University of Liege, Liege, Belgium; Bioinformatics and Modeling, GIGA-R, University of Liege, Liege, Belgium.
authors.forename: Kristel
authors.initials: K
authors.lastname: Van Steen
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Henderson
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Pediatric Pulmonology and Pediatric Allergology, Beatrix Children's Hospital, GRIAC Research Institute, Groningen, The Netherlands. Electronic address: g.h.koppelman@umcg.nl.
authors.forename: Gerard H
authors.initials: GH
authors.lastname: Koppelman
mesh_terms: D001249:Asthma / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004843:Epistasis, Genetic; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D053577:Interleukin-1 Receptor Accessory Protein / Q000235:genetics / Q000276:immunology; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D007378:Interleukins / Q000235:genetics* / Q000276:immunology; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000276:immunology; D020641:Polymorphism, Single Nucleotide; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000276:immunology; D017472:Receptors, Interleukin-1 / Q000235:genetics / Q000276:immunology; D012135:Respiratory Sounds / Q000276:immunology / Q000503:physiopathology*; D015398:Signal Transduction
chemical_list: C507765:IL1RAP protein, human; C079241:IL1RL1 protein, human; C506536:IL33 protein, human; D053577:Interleukin-1 Receptor Accessory Protein; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D007378:Interleukins; C507779:MYD88 protein, human; D008562:Membrane Glycoproteins; D053594:Myeloid Differentiation Factor 88; D011956:Receptors, Cell Surface; D017472:Receptors, Interleukin-1; C434984:TIRAP protein, human
keywords: Avon Longitudinal Study of Parents and Children study; IL1RL1; IL33; IL33-IL1RL1 pathway; Prevalence and Incidence of Asthma and Mite Allergy study; asthma; children; wheezing phenotypes