Determining the contribution of IL33 and IL1RL1 polymorphisms to clinical and immunological features of asthma

Portelli, Michael A., Bennett, Neil D., Hankinson, Jenny, Ntalla, Ioanna, Henry, Amanda, Billington, Charlotte K., Shaw, Dominick, Pogson, Zara E.K., Fogarty, Andrew, McKeever, Tricia, Jonker, Leon, Singapuri, Amisha, Heaney, Liam, Mansur, Adel, Thomson, Neil C., Chaudhuri, Rekha, Holloway, John, Lockett, Gabrielle, Howarth, Peter, Niven, Rob, Tobin, Martin D., Wain, Louise, Hall, Ian P., Brightling, Chris E., Simpson, Angela and Sayers, Ian (2016) Determining the contribution of IL33 and IL1RL1 polymorphisms to clinical and immunological features of asthma. American Journal of Respiratory and Critical Care Medicine, 193 . A2922.

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Official URL: http://www.atsjournals.org/doi/abs/10.1164/ajrccm-...

Abstract

Rationale: IL33 (9p24.1) and the IL33 receptor (IL1RL, 2q12) have been reproducibly identified as asthma susceptibility genes. However, the variants driving genetic associations are not yet fully defined. Using a population based birth cohort of 1059 children (Manchester Asthma and Allergy Study-(MAAS)) and 2536 adults with asthma (Genetics of Asthma Severity and Phenotypes- (GASP)) cohort we aimed to define genetic variants associated with clinical and immunological features of asthma.

Methods: MAAS samples were genotyped using the Illumina 610 Quad array and imputed using 1000G reference panel. GASP samples were genotyped using two custom designed Affymetrix arrays (UK BiLEVE/UK Biobank array). Datasets were quality controlled for gender mismatches, outliers and relatedness. Data was generated for the IL33/IL1RL1 regions consisting of the genes and surrounding regions (chr9:5715785−6757983 & chr2:102427961−103468497) on the following traits: asthma diagnosis (MAAS), atopy, FEV1 (GASP) and FEV1/FVC (MAAS and GASP) as well as total blood eosinophil counts and serum total IgE levels (GASP). Variables for blood eosinophils and total IgE were log10 transformed. Analysis was carried out in PLINK using linear or logistic regression modelling including appropriate covariates for each trait.

Results: In the MAAS cohort, we replicated the association of the IL33 locus with asthma diagnosis, identifying potentially two independent novel signals in that locus (rs10975398; P=1.70E-05; B= -1.519; MAF=0.32 and rs2890697; P=1.10E-04; B= -1.573; MAF=0.43). This association survived a Bonferroni correction for multiple testing. Although not surviving correction, an association was also identified for atopy in the IL1RL1 locus for MAAS (P=1.08E-04; MAF=0.48). In GASP we identified modest associations not in known LD with published loci (P-value range: 5.00E-02 – 7.60E-04) for FEV1, FEV1/FVC, atopy, blood eosinophils and total IgE in both the IL33 and IL1RL1 loci. Multiple SNPs presented nominal association (P<0.01) with more than one trait such as atopy & total IgE, providing supporting evidence for association.

Conclusion: We replicated the association of IL33 region SNPs with asthma diagnosis in MAAS, highlighting the role of this locus in childhood asthma. Although trait association signals did not survive correction for multiple testing, nominal association across multiple phenotypes in GASP provides suggestive evidence of the role of the IL33/IL1RL1 genetic polymorphisms in determining clinical and immunological features of asthma.

Item Type: Article
Journal / Publication Title: American Journal of Respiratory and Critical Care Medicine
Publisher: American Thoracic Society
ISSN: 1535-4970
Departments: Research Office & Graduate School (ROGS)
Additional Information: Published abstract of a presentation at American Thoracic Society Conference, San Francisco, 16 May 2016.
Depositing User: Anna Lupton
Date Deposited: 13 Jul 2017 13:36
Last Modified: 10 Feb 2019 22:11
URI: http://insight.cumbria.ac.uk/id/eprint/3097

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