TY - JOUR
T1 - Phenotypic and functional translation of IL1RL1 locus polymorphisms in lung tissue and asthmatic airway epithelium
AU - Portelli, Michael A.
AU - Dijk, F. Nicole
AU - Ketelaar, Maria E.
AU - Shrine, Nick
AU - Hankinson, Jenny
AU - Bhaker, Sangita
AU - Grotenboer, Neomi S.
AU - Obeidat, Ma'en
AU - Henry, Amanda P.
AU - Billington, Charlotte K.
AU - Shaw, Dominick
AU - Johnson, Simon R.
AU - Pogson, Zara E. K.
AU - Fogarty, Andrew
AU - McKeever, Tricia M.
AU - Nickle, David C.
AU - Bosse, Yohan
AU - van den Berge, Maarten
AU - Faiz, Alen
AU - Brouwer, Sharon
AU - Vonk, Judith M.
AU - de Vos, Paul
AU - Brandsma, Corry-Anke
AU - Vermeulen, Cornelis J.
AU - Singapuri, Amisha
AU - Heaney, Liam G.
AU - Mansur, Adel H.
AU - Chaudhuri, Rekha
AU - Thomson, Neil C.
AU - Holloway, John W.
AU - Lockett, Gabrielle A.
AU - Howarth, Peter H.
AU - Niven, Robert
AU - Simpson, Angela
AU - Blakey, John D.
AU - Tobin, Martin D.
AU - Postma, Dirkje S.
AU - Hall, Ian P.
AU - Wain, Louise
AU - Nawijn, Martijn C.
AU - Brightling, Christopher E.
AU - Koppelman, Gerard H.
AU - Sayers, Ian
PY - 2020/4/23
Y1 - 2020/4/23
N2 - The IL1RL1 (ST2) gene locus is robustly associated with asthma; however, the contribution of single nucleotide polymorphisms (SNPs) in this locus to specific asthma subtypes and the functional mechanisms underlying these associations remain to be defined. We tested for association between IL1RL1 region SNPs and characteristics of asthma as defined by clinical and immunological measures and addressed functional effects of these genetic variants in lung tissue and airway epithelium. Utilizing 4 independent cohorts (Lifelines, Dutch Asthma GWAS [DAG], Genetics of Asthma Severity and Phenotypes [GASP], and Manchester Asthma and Allergy Study [MAAS]) and resequencing data, we identified 3 key signals associated with asthma features. Investigations in lung tissue and primary bronchial epithelial cells identified context-dependent relationships between the signals and IL1RL1 mRNA and soluble protein expression. This was also observed for asthma-associated IL1RL1 nonsynonymous coding TIR domain SNPs. Bronchial epithelial cell cultures from asthma patients, exposed to exacerbation-relevant stimulations, revealed modulatory effects for all 4 signals on IL1RL1 mRNA and/or protein expression, suggesting SNP-environment interactions. The IL1RL1 TIR signaling domain haplotype affected IL-33-driven NF-kappa B signaling, while not interfering with TLR signaling. In summary, we identify that IL1RL1 genetic signals potentially contribute to severe and eosinophilic phenotypes in asthma, as well as provide initial mechanistic insight, including genetic regulation of IL1RL1 isoform expression and receptor signaling.
AB - The IL1RL1 (ST2) gene locus is robustly associated with asthma; however, the contribution of single nucleotide polymorphisms (SNPs) in this locus to specific asthma subtypes and the functional mechanisms underlying these associations remain to be defined. We tested for association between IL1RL1 region SNPs and characteristics of asthma as defined by clinical and immunological measures and addressed functional effects of these genetic variants in lung tissue and airway epithelium. Utilizing 4 independent cohorts (Lifelines, Dutch Asthma GWAS [DAG], Genetics of Asthma Severity and Phenotypes [GASP], and Manchester Asthma and Allergy Study [MAAS]) and resequencing data, we identified 3 key signals associated with asthma features. Investigations in lung tissue and primary bronchial epithelial cells identified context-dependent relationships between the signals and IL1RL1 mRNA and soluble protein expression. This was also observed for asthma-associated IL1RL1 nonsynonymous coding TIR domain SNPs. Bronchial epithelial cell cultures from asthma patients, exposed to exacerbation-relevant stimulations, revealed modulatory effects for all 4 signals on IL1RL1 mRNA and/or protein expression, suggesting SNP-environment interactions. The IL1RL1 TIR signaling domain haplotype affected IL-33-driven NF-kappa B signaling, while not interfering with TLR signaling. In summary, we identify that IL1RL1 genetic signals potentially contribute to severe and eosinophilic phenotypes in asthma, as well as provide initial mechanistic insight, including genetic regulation of IL1RL1 isoform expression and receptor signaling.
KW - Genome-wide association
KW - Genetic risk-factors
KW - Interleukin-1 receptor
KW - Large-scale
KW - Hay-fever
KW - St2
KW - Variants
KW - Expression
KW - Il-33
KW - Differentiation
UR - https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=researchintelligenceproject&SrcAuth=WosAPI&KeyUT=WOS:000528336200005&DestLinkType=FullRecord&DestApp=WOS_CPL
U2 - 10.1172/jci.insight.132446
DO - 10.1172/jci.insight.132446
M3 - Article
C2 - 32324168
SN - 2379-3708
VL - 5
JO - JCI INSIGHT
JF - JCI INSIGHT
IS - 8
M1 - e132446
ER -