Phenotypic and functional translation of IL1RL1 locus polymorphisms in lung tissue and asthmatic airway epithelium
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-κB 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.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2020 |
|---|---|
| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:5 |
|---|---|
| Enthalten in: |
JCI insight - 5(2020), 8 vom: 23. Apr. |
| Sprache: |
Englisch |
|---|
| Links: |
|---|
| Themen: |
Asthma |
|---|
| Anmerkungen: |
Date Completed 17.05.2021 Date Revised 18.05.2022 published: Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1172/jci.insight.132446 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM309085381 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM309085381 | ||
| 003 | DE-627 | ||
| 005 | 20231225133133.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231225s2020 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1172/jci.insight.132446 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1030.xml |
| 035 | |a (DE-627)NLM309085381 | ||
| 035 | |a (NLM)32324168 | ||
| 035 | |a (PII)132446 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Portelli, Michael A |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Phenotypic and functional translation of IL1RL1 locus polymorphisms in lung tissue and asthmatic airway epithelium |
| 264 | 1 | |c 2020 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 17.05.2021 | ||
| 500 | |a Date Revised 18.05.2022 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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-κB 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Asthma | |
| 650 | 4 | |a Cell Biology | |
| 650 | 4 | |a Genetic variation | |
| 650 | 4 | |a Genetics | |
| 650 | 4 | |a Molecular genetics | |
| 650 | 7 | |a IL1RL1 protein, human |2 NLM | |
| 650 | 7 | |a Interleukin-1 Receptor-Like 1 Protein |2 NLM | |
| 700 | 1 | |a Dijk, F Nicole |e verfasserin |4 aut | |
| 700 | 1 | |a Ketelaar, Maria E |e verfasserin |4 aut | |
| 700 | 1 | |a Shrine, Nick |e verfasserin |4 aut | |
| 700 | 1 | |a Hankinson, Jenny |e verfasserin |4 aut | |
| 700 | 1 | |a Bhaker, Sangita |e verfasserin |4 aut | |
| 700 | 1 | |a Grotenboer, Néomi S |e verfasserin |4 aut | |
| 700 | 1 | |a Obeidat, Ma'en |e verfasserin |4 aut | |
| 700 | 1 | |a Henry, Amanda P |e verfasserin |4 aut | |
| 700 | 1 | |a Billington, Charlotte K |e verfasserin |4 aut | |
| 700 | 1 | |a Shaw, Dominick |e verfasserin |4 aut | |
| 700 | 1 | |a Johnson, Simon R |e verfasserin |4 aut | |
| 700 | 1 | |a Pogson, Zara Ek |e verfasserin |4 aut | |
| 700 | 1 | |a Fogarty, Andrew |e verfasserin |4 aut | |
| 700 | 1 | |a McKeever, Tricia M |e verfasserin |4 aut | |
| 700 | 1 | |a Nickle, David C |e verfasserin |4 aut | |
| 700 | 1 | |a Bossé, Yohan |e verfasserin |4 aut | |
| 700 | 1 | |a van den Berge, Maarten |e verfasserin |4 aut | |
| 700 | 1 | |a Faiz, Alen |e verfasserin |4 aut | |
| 700 | 1 | |a Brouwer, Sharon |e verfasserin |4 aut | |
| 700 | 1 | |a Vonk, Judith M |e verfasserin |4 aut | |
| 700 | 1 | |a de Vos, Paul |e verfasserin |4 aut | |
| 700 | 1 | |a Brandsma, Corry-Anke |e verfasserin |4 aut | |
| 700 | 1 | |a Vermeulen, Cornelis J |e verfasserin |4 aut | |
| 700 | 1 | |a Singapuri, Amisha |e verfasserin |4 aut | |
| 700 | 1 | |a Heaney, Liam G |e verfasserin |4 aut | |
| 700 | 1 | |a Mansur, Adel H |e verfasserin |4 aut | |
| 700 | 1 | |a Chaudhuri, Rekha |e verfasserin |4 aut | |
| 700 | 1 | |a Thomson, Neil C |e verfasserin |4 aut | |
| 700 | 1 | |a Holloway, John W |e verfasserin |4 aut | |
| 700 | 1 | |a Lockett, Gabrielle A |e verfasserin |4 aut | |
| 700 | 1 | |a Howarth, Peter H |e verfasserin |4 aut | |
| 700 | 1 | |a Niven, Robert |e verfasserin |4 aut | |
| 700 | 1 | |a Simpson, Angela |e verfasserin |4 aut | |
| 700 | 1 | |a Blakey, John D |e verfasserin |4 aut | |
| 700 | 1 | |a Tobin, Martin D |e verfasserin |4 aut | |
| 700 | 1 | |a Postma, Dirkje S |e verfasserin |4 aut | |
| 700 | 1 | |a Hall, Ian P |e verfasserin |4 aut | |
| 700 | 1 | |a Wain, Louise V |e verfasserin |4 aut | |
| 700 | 1 | |a Nawijn, Martijn C |e verfasserin |4 aut | |
| 700 | 1 | |a Brightling, Christopher E |e verfasserin |4 aut | |
| 700 | 1 | |a Koppelman, Gerard H |e verfasserin |4 aut | |
| 700 | 1 | |a Sayers, Ian |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t JCI insight |d 2016 |g 5(2020), 8 vom: 23. Apr. |w (DE-627)NLM257703918 |x 2379-3708 |7 nnns |
| 773 | 1 | 8 | |g volume:5 |g year:2020 |g number:8 |g day:23 |g month:04 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1172/jci.insight.132446 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 5 |j 2020 |e 8 |b 23 |c 04 | ||