Moderate-to-severe asthma in individuals of European ancestry: a genome-wide association study

Shrine, Nick; Portelli, Michael A.; John, Catherine; Soler Artigas, Mar�a; Bennett, Neil; Hall, Robert; Lewis, Jon; Henry, Amanda P.; Billington, Charlotte K.; Ahmad, Azaz; Packer, Richard J.; Shaw, Dominick; Pogson, Zara E.K.; Fogarty, Andrew; McKeever, Tricia M.; Singapuri, Amisha; Heaney, Liam G.; Mansur, Adel H.; Chaudhuri, Rekha; Thomson, Neil C.; Holloway, John W.; Lockett, Gabrielle A.; Howarth, Peter H.; Djukanovic, Ratko; Hankinson, Jenny; Niven, Robert; Simpson, Angela; Fan Chung, Kian; Sterk, Peter J.; Blakey, John D.; Adcock, Ian M.; Hu, Sile; Guo, Yike; Obeidat, Maen; Sin, Don D.; van den Berge, Maarten; Nickle, David C.; Boss�, Yohan; Tobin, Martin D.; Hall, Ian P.; Brightling, Christopher E.; Wain, Louise V.; Sayers, Ian

Abstract

Background
Few genetic studies that focus on moderate-to-severe asthma exist. We aimed to identity novel genetic variants associated with moderate-to-severe asthma, see whether previously identified genetic variants for all types of asthma contribute to moderate-to-severe asthma, and provide novel mechanistic insights using expression analyses in patients with asthma.

Methods
In this genome-wide association study, we used a two-stage case-control design. In stage 1, we genotyped patient-level data from two UK cohorts (the Genetics of Asthma Severity and Phenotypes [GASP] initiative and the Unbiased BIOmarkers in PREDiction of respiratory disease outcomes [U-BIOPRED] project) and used data from the UK Biobank to collect patient-level genomic data for cases and controls of European ancestry in a 1:5 ratio. Cases were defined as having moderate-to-severe asthma if they were taking appropriate medication or had been diagnosed by a doctor. Controls were defined as not having asthma, rhinitis, eczema, allergy, emphysema, or chronic bronchitis as diagnosed by a doctor. For stage 2, an independent cohort of cases and controls (1:5) was selected from the UK Biobank only, with no overlap with stage 1 samples. In stage 1 we undertook a genome-wide association study of moderate-to-severe asthma, and in stage 2 we followed up independent variants that reached the significance threshold of p less than 1 × 10−6 in stage 1. We set genome-wide significance at p less than 5 × 10−8. For novel signals, we investigated their effect on all types of asthma (mild, moderate, and severe). For all signals meeting genome-wide significance, we investigated their effect on gene expression in patients with asthma and controls.

Findings
We included 5135 cases and 25 675 controls for stage 1, and 5414 cases and 21 471 controls for stage 2. We identified 24 genome-wide significant signals of association with moderate-to-severe asthma, including several signals in innate or adaptive immune-response genes. Three novel signals were identified: rs10905284 in GATA3 (coded allele A, odds ratio [OR] 0·90, 95% CI 0·88–0·93; p=1·76 × 10−10), rs11603634 in the MUC5AC region (coded allele G, OR 1·09, 1·06–1·12; p=2·32 × 10−8), and rs560026225 near KIAA1109 (coded allele GATT, OR 1·12, 1·08–1·16; p=3·06 × 10−9). The MUC5AC signal was not associated with asthma when analyses included mild asthma. The rs11603634 G allele was associated with increased expression of MUC5AC mRNA in bronchial epithelial brush samples via proxy SNP rs11602802; (p=2·50 × 10−5) and MUC5AC mRNA was increased in bronchial epithelial samples from patients with severe asthma (in two independent analyses, p=0·039 and p=0·022).

Interpretation
We found substantial shared genetic architecture between mild and moderate-to-severe asthma. We also report for the first time genetic variants associated with the risk of developing moderate-to-severe asthma that regulate mucin production. Finally, we identify candidate causal genes in these loci and provide increased insight into this difficult to treat population.

Citation

Shrine, N., Portelli, M. A., John, C., Soler Artigas, M., Bennett, N., Hall, R., Lewis, J., Henry, A. P., Billington, C. K., Ahmad, A., Packer, R. J., Shaw, D., Pogson, Z. E., Fogarty, A., McKeever, T. M., Singapuri, A., Heaney, L. G., Mansur, A. H., Chaudhuri, R., Thomson, N. C., …Sayers, I. (2019). Moderate-to-severe asthma in individuals of European ancestry: a genome-wide association study. Lancet Respiratory Medicine, 7(1), 20-34. https://doi.org/10.1016/S2213-2600%2818%2930389-8

• Journal Article Type: Article
• Acceptance Date: Sep 13, 2018
• Online Publication Date: Dec 11, 2018
• Publication Date: Jan 1, 2019
• Deposit Date: Oct 29, 2018
• Publicly Available Date: Dec 13, 2018
• Journal: The Lancet Respiratory Medicine
• Print ISSN: 2213-2600
• Electronic ISSN: 2213-2619
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 7
• Issue: 1
• Pages: 20-34
• DOI: https://doi.org/10.1016/S2213-2600%2818%2930389-8
• Public URL: https://nottingham-repository.worktribe.com/output/1207160
• Publisher URL: https://www.sciencedirect.com/science/article/pii/S2213260018303898?via%3Dihub
• Additional Information: This article is maintained by: Elsevier; Article Title: Moderate-to-severe asthma in individuals of European ancestry: a genome-wide association study; Journal Title: The Lancet Respiratory Medicine; CrossRef DOI link to publisher maintained version: https://doi.org/10.1016/S2213-2600(18)30389-8; CrossRef DOI link to the associated document: https://doi.org/10.1016/S2213-2600(18)30447-8; Content Type: article; Copyright: © 2018 The Author(s). Published by Elsevier Ltd.
• Contract Date: Oct 29, 2018