A genome-wide analysis of the response to inhaled β2-agonists in chronic obstructive pulmonary disease.

C Crim, C P Hersh, T H Beaty, J D Crapo, J E Hokanson, B J Make, E A Regan, J Ramsdell, V Kim, S P Bhatt, P Bakke, E Wouters, S Rennard, M Hardin, B Celli, P M A Calverley, A Agusti, J C Yates, J Vestbo, W MacNee, H O Coxson, D A Lomas, E Wan, M-L McDonald, M H Cho

Journal: The pharmacogenomics journal 2017;16(4):326-35

PMID: 26503814

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Abstract

Short-acting β2-agonist bronchodilators are the most common medications used in treating chronic obstructive pulmonary disease (COPD). Genetic variants determining bronchodilator responsiveness (BDR) in COPD have not been identified. We performed a genome-wide association study (GWAS) of BDR in 5789 current or former smokers with COPD in one African-American and four white populations. BDR was defined as the quantitative spirometric response to inhaled β2-agonists. We combined results in a meta-analysis. In the meta-analysis, single-nucleotide polymorphisms (SNPs) in the genes KCNK1 (P=2.02 × 10(-7)) and KCNJ2 (P=1.79 × 10(-7)) were the top associations with BDR. Among African Americans, SNPs in CDH13 were significantly associated with BDR (P=5.1 × 10(-9)). A nominal association with CDH13 was identified in a gene-based analysis in all subjects. We identified suggestive association with BDR among COPD subjects for variants near two potassium channel genes (KCNK1 and KCNJ2). SNPs in CDH13 were significantly associated with BDR in African Americans.The Pharmacogenomics Journal advance online publication, 27 October 2015; doi:10.1038/tpj.2015.65.

Address: Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.; Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.; Wolfson Institute for Biomedical Research, University College London, London, UK.; UBC Department of Radiology, Vancouver General Hospital, Vancouver, Canada.; Centre for Inflammation Research, University of Edinburgh, Edinburgh, Scotland, UK.; Department of Respiratory Medicine, Manchester Academic Health Sciences Centre, University Hospital of South Manchester, Manchester, UK.; GlaxoSmithKline, Research Triangle Park, NC, USA.; Thorax Institute, Hospital Clinic, IDIBAPS, Univ Barcelona and CIBERES, Barcelona, Spain.; Department of Pulmonary and Rehabilitation Medicine, University of Liverpool, Liverpool, UK.; Pulmonary and Critical Care Division, Department of Medicine, University of Nebraska, Omaha, NE, USA.; Center for Chronic Diseases, University Hospital Maastricht, Maastricht, The Netherlands.; Department of Clinical Science, University of Bergen, Bergen, Norway.; Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama, Birmingham, AL, USA.; Division of Pulmonary and Critical Care, Temple University Hospital, Philadelphia, PA, USA.; University of California, San Diego, San Diego, CA, USA.; Division of Pulmonary Sciences and Critical Care Medicine, National Jewish Health, Denver, CO, USA.; Department of Epidemiology, Colorado School of Public Health, University of Colorado Denver, Denver, CO, USA.; Johns Hopkins School of Public Health, Baltimore, MD, USA.

DOI: 10.1038/tpj.2015.65