Phenotypic and functional translation of IL1RL1 locus polymorphisms in lung tissue and asthmatic airway epithelium
Michael A. Portelli, … , Gerard H. Koppelman, Ian Sayers
Michael A. Portelli, … , Gerard H. Koppelman, Ian Sayers
Published April 23, 2020
Citation Information: JCI Insight. 2020;5(8):e132446. https://doi.org/10.1172/jci.insight.132446.
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Research Article Cell biology Genetics

Phenotypic and functional translation of IL1RL1 locus polymorphisms in lung tissue and asthmatic airway epithelium

Abstract

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.

Authors

Michael A. Portelli, F. Nicole Dijk, Maria E. Ketelaar, Nick Shrine, Jenny Hankinson, Sangita Bhaker, Néomi S. Grotenboer, Ma’en Obeidat, Amanda P. Henry, Charlotte K. Billington, Dominick Shaw, Simon R. Johnson, Zara E.K. Pogson, Andrew Fogarty, Tricia M. McKeever, David C. Nickle, Yohan Bossé, Maarten van den Berge, Alen Faiz, Sharon Brouwer, Judith M. Vonk, Paul de Vos, Corry-Anke Brandsma, Cornelis J. Vermeulen, Amisha Singapuri, Liam G. Heaney, Adel H. Mansur, Rekha Chaudhuri, Neil C. Thomson, John W. Holloway, Gabrielle A. Lockett, Peter H. Howarth, Robert Niven, Angela Simpson, John D. Blakey, Martin D. Tobin, Dirkje S. Postma, Ian P. Hall, Louise V. Wain, Martijn C. Nawijn, Christopher E. Brightling, Gerard H. Koppelman, Ian Sayers

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Figure 3

Baseline IL1RL1 mRNA and soluble IL1RL1 protein levels are driven by SNPs in cultured human bronchial epithelial cells.

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Baseline IL1RL1 mRNA and soluble IL1RL1 protein levels are driven by SNP...
(A and B) In cultured HBECs, the lower level of IL1RL1 soluble and transmembrane mRNA can be observed in carriers of the risk allele (A) for lower lung function (FEV1) for Signal B (rs4142132; A [AA, n = 6; AG, n = 11; GG, n = 12] and B [AA, n = 7; AG, n = 11; GG, n = 12]; P < 0.05). (C and D) Increased levels of total and transmembrane IL1RL1 mRNA was observed for carriers of the asthma risk allele (A) in Signal C (rs17027258, proxy for rs72825929; C [AA, n = 17; AG/GG, n = 10] and D [AA, n = 19; AG/GG, n = 12]; P < 0.05). (E–G) Changes in mRNA levels were reflected in soluble IL1RL1 protein levels in matched cellular supernatants (F [TT, n = 7; TC, n = 10; CC, n = 11] and G [AA, n = 16; AG/GG, n = 12]; P < 0.05); in Signal A, carriers of the asthma risk/elevated blood eosinophil levels allele of SNP rs995514 (proxy for rs12474258) (T) presented with lower levels of IL1RL1 soluble protein (E [TT, n = 4; TC, n = 13; CC, n = 11]; P = 0.002). However, this was not observed at the RNA level (Supplemental Figure 3). Statistics were run using Mann-Whitney U test (C, D, and G) or Kruskal-Wallis test (A, B, E, and F), as relevant. Data are represented by Tukey box and whisker plots, where the box covers data from the 25th to the 75th percentiles, with the center line denoting the median of the data. Whisker plots identify the interquartile range as determined by the Tukey method, with resulting outlier data displayed as distinct points outside the whiskers.