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

Nick Shrine(University of Leicester), Michael A. Portelli(University of Nottingham), Catherine John(University of Leicester), María Soler Artigas(University of Leicester), Neil Bennett(University of Leicester), Robert J. Hall(University of Nottingham), Jon Lewis(University of Nottingham), Amanda P. Henry(University of Nottingham), Charlotte K. Billington(University of Nottingham), Azaz Ahmad(University of Nottingham), Richard Packer(University of Leicester), Dominick Shaw(University of Nottingham), Zara Pogson(University of Nottingham), Andrew Fogarty(University of Nottingham), Tricia M. McKeever(University of Nottingham), Amisha Singapuri(University of Leicester), Liam G. Heaney(Queen's University Belfast), Adel Mansur(Heartlands Hospital), Rekha Chaudhuri(University of Glasgow), Neil C. Thomson(University of Glasgow), John W. Holloway(University of Southampton), Gabrielle A. Lockett(University of Southampton), Peter Howarth(University of Southampton), Ratko Djukanović(University of Southampton), Jenny Hankinson(Manchester Academic Health Science Centre), Robert Niven(Manchester Academic Health Science Centre), Angela Simpson(Manchester Academic Health Science Centre), Kian Fan Chung(Imperial College London), Peter J. Sterk(University of Amsterdam), John Blakey(Sir Charles Gairdner Hospital), Ian M. Adcock(Imperial College London), Sile Hu(Imperial College London), Yike Guo(Imperial College London), Ma’en Obeidat(University of British Columbia), Don D. Sin(University of British Columbia), Maarten van den Berge(University Medical Center Groningen), David C. Nickle(Merck & Co., Inc., Rahway, NJ, USA (United States)), Yohan Bossé(Institut universitaire de cardiologie et de pneumologie de Québec), Martin D. Tobin(University of Leicester), Ian P. Hall(University of Nottingham), Christopher E. Brightling(University of Leicester), Louise V. Wain(University of Leicester), Ian Sayers(University of Nottingham)
The Lancet Respiratory Medicine
December 11, 2018
10.1016/s2213-2600(18)30389-8
Cited by 256Open Access
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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. METHODS: . 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: ) 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.

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