Moderate-to-severe asthma in individuals of European ancestry: a genome-wide association study. Issue 1 (January 2019)

• Record Type: Journal Article
• Authors: Shrine, Nick; Portelli, Michael A; John, Catherine; Soler Artigas, María; 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; Chung, Kian Fan; 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; Bossé, Yohan; Tobin, Martin D; Hall, Ian P; Brightling, Christopher E; Wain, Louise V; Sayers, Ian;
• Is Part Of: Lancet. Volume 7:Issue 1(2019)
• Page Start: 20
• Page End: 34
• Publication Date: 2019-01
• Subjects: Respiratory organs -- Diseases -- Periodicals; 616.2005
• DOI: 10.1016/S2213-2600(18)30389-8
• Languages: English
• ISSNs: 2213-2600

Abstract

Summary: 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.