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

Olga E. Savenije; Jestinah M. Mahachie John; Raquel Granell; Marjan Kerkhof; F. Nicole Dijk; Johan C. de Jongste; Henriette A. Smit; Bert Brunekreef; Dirkje S. Postma; Kristel Van Steen; John Henderson; Gerard H. Koppelman

doi:10.1016/j.jaci.2013.12.1080

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

Olga E. Savenije, Jestinah M. Mahachie John, Raquel Granell, Marjan Kerkhof, F. Nicole Dijk, Johan C. de Jongste, Henriette A. Smit, Bert Brunekreef, Dirkje S. Postma, Kristel Van Steen, John Henderson, Gerard H. Koppelman^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Pages (from-to)	170-177
Number of pages	8
Journal	Journal of Allergy and Clinical Immunology
Volume	134
Issue number	1
DOIs	https://doi.org/10.1016/j.jaci.2013.12.1080
Publication status	Published - Jul 2014

Funding

The PIAMA study was supported by the Gratama Foundation (grant 10.21), the Dutch Asthma Foundation (grants 3.4.01.26, 3.2.06.022, and 3.2.09.081JU), the ZonMw Netherlands (grant 912-03-031), and the ministry of the environment. O.E.S. was supported by a ZonMw AGIKO-fund (grant 92003555). The UK Medical Research Council and the Welcome Trust (grant reference 092731) and the University of Bristol provide core support for ALSPAC. J.M.M.J. and K. V. S. acknowledge research opportunities offered by the Belgium Network DYSCO (Dynamical Systems, Control, and Optimization), which is funded by the Interuniversity Attraction Poles Programme and initiated by the Belgian State Science Policy Office. Their work was also supported by in part by the IST Programme of the European Community under the PASCAL2 Network of Excellence (Pattern Analysis, Statistical Modelling and Computational Learning), IST-2007-216886.

Keywords

IL33-IL1RL1 pathway
asthma
wheezing phenotypes
children
IL1RL1
IL33
Avon Longitudinal Study of Parents and Children study
Prevalence and Incidence of Asthma and Mite Allergy study
GENOME-WIDE ASSOCIATION
1ST 6 YEARS
GENETIC-VARIATION
BIRTH COHORT
DISEASE
ATOPY
IL-33
LIFE

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Savenije, O. E., John, J. M. M., Granell, R., Kerkhof, M., Dijk, F. N., de Jongste, J. C., Smit, H. A., Brunekreef, B., Postma, D. S., Van Steen, K., Henderson, J., & Koppelman, G. H. (2014). Association of IL33-IL-1 receptor-like 1 (IL1RL1) pathway polymorphisms with wheezing phenotypes and asthma in childhood. Journal of Allergy and Clinical Immunology, 134(1), 170-177. https://doi.org/10.1016/j.jaci.2013.12.1080

@article{518da24c33df45b1bfb312c48b5a2f52,

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.",

keywords = "IL33-IL1RL1 pathway, asthma, wheezing phenotypes, children, IL1RL1, IL33, Avon Longitudinal Study of Parents and Children study, Prevalence and Incidence of Asthma and Mite Allergy study, GENOME-WIDE ASSOCIATION, 1ST 6 YEARS, GENETIC-VARIATION, BIRTH COHORT, DISEASE, ATOPY, IL-33, LIFE",

author = "Savenije, {Olga E.} and John, {Jestinah M. Mahachie} and Raquel Granell and Marjan Kerkhof and Dijk, {F. Nicole} and {de Jongste}, {Johan C.} and Smit, {Henriette A.} and Bert Brunekreef and Postma, {Dirkje S.} and {Van Steen}, Kristel and John Henderson and Koppelman, {Gerard H.}",

year = "2014",

month = jul,

doi = "10.1016/j.jaci.2013.12.1080",

language = "English",

volume = "134",

pages = "170--177",

journal = "Journal of Allergy and Clinical Immunology",

issn = "0091-6749",

publisher = "Elsevier Inc.",

number = "1",

}

Savenije, OE, John, JMM, Granell, R, Kerkhof, M, Dijk, FN, de Jongste, JC, Smit, HA, Brunekreef, B, Postma, DS, Van Steen, K, Henderson, J & Koppelman, GH 2014, 'Association of IL33-IL-1 receptor-like 1 (IL1RL1) pathway polymorphisms with wheezing phenotypes and asthma in childhood', Journal of Allergy and Clinical Immunology, vol. 134, no. 1, pp. 170-177. https://doi.org/10.1016/j.jaci.2013.12.1080

TY - JOUR

T1 - Association of IL33-IL-1 receptor-like 1 (IL1RL1) pathway polymorphisms with wheezing phenotypes and asthma in childhood

AU - Savenije, Olga E.

AU - John, Jestinah M. Mahachie

AU - Granell, Raquel

AU - Kerkhof, Marjan

AU - Dijk, F. Nicole

AU - de Jongste, Johan C.

AU - Smit, Henriette A.

AU - Brunekreef, Bert

AU - Postma, Dirkje S.

AU - Van Steen, Kristel

AU - Henderson, John

AU - Koppelman, Gerard H.

PY - 2014/7

Y1 - 2014/7

N2 - 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.

AB - 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.

KW - IL33-IL1RL1 pathway

KW - asthma

KW - wheezing phenotypes

KW - children

KW - IL1RL1

KW - IL33

KW - Avon Longitudinal Study of Parents and Children study

KW - Prevalence and Incidence of Asthma and Mite Allergy study

KW - GENOME-WIDE ASSOCIATION

KW - 1ST 6 YEARS

KW - GENETIC-VARIATION

KW - BIRTH COHORT

KW - DISEASE

KW - ATOPY

KW - IL-33

KW - LIFE

U2 - 10.1016/j.jaci.2013.12.1080

DO - 10.1016/j.jaci.2013.12.1080

M3 - Article

SN - 0091-6749

VL - 134

SP - 170

EP - 177

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

IS - 1

ER -

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

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Keywords

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