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

Title: Moderate-to-severe asthma in individuals of European ancestry: a genome-wide association study
Authors: Shrine, N
Portelli, MA
John, C
Soler Artigas, M
Bennett, N
Hall, R
Lewis, J
Henry, AP
Billington, CK
Ahmad, A
Packer, RJ
Shaw, D
Pogson, ZEK
Fogarty, A
McKeever, TM
Singapuri, A
Heaney, LG
Mansur, AH
Chaudhuri, R
Thomson, NC
Holloway, JW
Lockett, GA
Howarth, PH
Djukanovic, R
Hankinson, J
Niven, R
Simpson, A
Chung, KF
Sterk, PJ
Blakey, JD
Adcock, IM
Hu, S
Guo, Y
Obeidat, M
Sin, DD
Van den Berge, M
Nickle, DC
Bossé, Y
Tobin, MD
Hall, IP
Brightling, CE
Wain, LV
Sayers, I
Item Type: Journal Article
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. FUNDING: Asthma UK, AirPROM, U-BIOPRED, UK Medical Research Council, and Rosetrees Trust.
Issue Date: 1-Jan-2019
Date of Acceptance: 13-Sep-2018
URI: http://hdl.handle.net/10044/1/65188
DOI: https://dx.doi.org/10.1016/S2213-2600(18)30389-8
ISSN: 2213-2600
Publisher: Elsevier
Start Page: 20
End Page: 34
Journal / Book Title: Lancet Respiratory Medicine
Volume: 7
Issue: 1
Copyright Statement: © 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license (https://creativecommons.org/licenses/by/4.0/)
Sponsor/Funder: Commission of the European Communities
Funder's Grant Number: 115010
Publication Status: Published
Conference Place: England
Online Publication Date: 2018-12-11
Appears in Collections:National Heart and Lung Institute
Airway Disease
Faculty of Medicine



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