Shrine, Nick, Portelli, Michael A, John, Catherine, Soler Artigas, María, Bennett, Neil, Hall, Robert, Lewis, Jon, Henry, Amanda P, Billington, Charlotte K, Ahmad, Azaz et al (show 33 more authors)
(2018)
Moderate-to-severe asthma in individuals of European ancestry: a genome-wide association study.
The Lancet. Respiratory medicine, 7 (1).
pp. 20-34.
Abstract
<h4>Background</h4>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.<h4>Methods</h4>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<sup>-6</sup> in stage 1. We set genome-wide significance at p less than 5 × 10<sup>-8</sup>. 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.<h4>Findings</h4>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<sup>-10</sup>), rs11603634 in the MUC5AC region (coded allele G, OR 1·09, 1·06-1·12; p=2·32 × 10<sup>-8</sup>), and rs560026225 near KIAA1109 (coded allele GATT, OR 1·12, 1·08-1·16; p=3·06 × 10<sup>-9</sup>). 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<sup>-5</sup>) 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).<h4>Interpretation</h4>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.<h4>Funding</h4>Asthma UK, AirPROM, U-BIOPRED, UK Medical Research Council, and Rosetrees Trust.
Item Type: | Article |
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Uncontrolled Keywords: | Humans, Asthma, Genetic Predisposition to Disease, Proteins, Severity of Illness Index, Case-Control Studies, Genotype, Adult, Aged, Middle Aged, Female, Male, GATA3 Transcription Factor, Genome-Wide Association Study, Mucin 5AC, White People |
Divisions: | Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Infection, Veterinary and Ecological Sciences |
Depositing User: | Symplectic Admin |
Date Deposited: | 07 Jun 2021 09:15 |
Last Modified: | 18 Jan 2023 22:36 |
DOI: | 10.1016/s2213-2600(18)30389-8 |
Open Access URL: | https://doi.org/10.1016/S2213-2600(18)30389-8 |
Related URLs: | |
URI: | https://livrepository.liverpool.ac.uk/id/eprint/3125409 |