| Title: | Moderate-to-severe asthma in individuals of European ancestry: a genome-wide association study |
| Journal: | The Lancet Respiratory Medicine |
| Published: | 11 Dec 2018 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/30552067/ |
| DOI: | https://doi.org/10.1016/s2213-2600(18)30389-8 |
| URL: | http://www.thelancet.com/article/S2213260018303898/pdf |
Publication 13752
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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.</p>
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.</p>
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).</p>
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.</p>
FUNDING: Asthma UK, AirPROM, U-BIOPRED, UK Medical Research Council, and Rosetrees Trust.</p>
16 Keywords
- Adult
- Aged
- Asthma
- Case-Control Studies
- Female
- GATA3 Transcription Factor
- Genetic Predisposition to Disease
- Genome-Wide Association Study
- Genotype
- Humans
- Male
- Middle Aged
- Mucin 5AC
- Proteins
- Severity of Illness Index
- White People
43 Authors
- Nick Shrine
- Michael A Portelli
- Catherine John
- María Soler Artigas
- Neil Bennett
- Robert Hall
- Jon Lewis
- Amanda P Henry
- Charlotte K Billington
- Azaz Ahmad
- Richard J Packer
- Dominick Shaw
- Zara E K Pogson
- Andrew Fogarty
- Tricia M McKeever
- Amisha Singapuri
- Liam G Heaney
- Adel H Mansur
- Rekha Chaudhuri
- Neil C Thomson
- John W Holloway
- Gabrielle A Lockett
- Peter H Howarth
- Ratko Djukanovic
- Jenny Hankinson
- Robert Niven
- Angela Simpson
- Kian Fan Chung
- Peter J Sterk
- John D Blakey
- Ian M Adcock
- Sile Hu
- Yike Guo
- Maen Obeidat
- Don D Sin
- Maarten van den Berge
- David C Nickle
- Yohan Bossé
- Martin D Tobin
- Ian P Hall
- Christopher E Brightling
- Louise V Wain
- Ian Sayers
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