A Genome-wide meta-analysis of the response to inhaled bronchodilators among subjects with chronic obstructive pulmonary disease. M. Hardin1,2, M. H. Cho1,2, M. McDonald1, E. Wan1,2, D. A. Lomas3, H. O. Coxson4, L. D. Edwards5, W. MacNee6, J. Vestbo7, J. C. Yates5, A. Agusti8, P. Calverley9, B. Celli2, C. Crim5, S. Rennard10, E. Wouters11, P. Bakke12, E. A. Regan13, B. Make13, A. Litonjua1,2, J. E. Hokanson14, J. D. Crapo13, T. H. Beaty15, E. K. Silberman1,2, C. P. Hersh1,2, the ECLIPSE and COPDGene Investigators 1) Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA; 2) Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA; 3) Department of Medicine, University COllege London, London, UK; 4) UBC Department of Radiology, Vancouver General Hospital, Vancouver, Canada; 5) GLaxoSmithKline, Research Triangle Park, NC, USA; 6) Department of Respiratory and Environmental Medcine, University of Edinburgh, Edinburgh, Scotland; 7) Department of Respiratory Medicine, Manchester Academic Health Sciences Centre, University Hospital of South Manchester, Manchester, UK; 8) Thoracic Institute, Hospital Clinic, Barcelona, SP; 9) Department of Pulmonaryr and Rehabilitation Medicine, University of Liverpool, Liverpool, UK; 10) Department of Medicine, Nebraska Medcial Center, Omaha, Nebraska, USA; 11) Center for Chronic Diseases, University Hospital Maastricht, Maastricht, The Netherlands; 12) Department of Clinical Science, University of Bergen, Bergen, Norway; 13) DIvision of Pulmonary and Critical Care Medicine, National Jewish Health, Denver, CO, USA; 14) Department of Epidemiology, Colorado School of PUblic Health, University of Colorado Denver, Denver, Colorado; 15) Johns Hopkins School of Public Health, Baltimore, MD, USA.

   Rationale: Recent genome-wide association studies have identified genes associated with lung function, both in population-based and chronic obstructive pulmonary disease (COPD) case/control cohorts. The response to inhaled bronchodilators is a measure of lung function that correlates with FEV1 decline and survival in COPD and has been found to be heritable. Identifying single nucleotide polymorphisms (SNPs) associated with bronchodilator responsiveness (BDR) may reveal novel genetic pathways associated with the pathogenesis of COPD. Methods: We performed a genome-wide association study of BDR in four cohorts of Caucasian subjects with GOLD stage II or higher COPD. These previously described cohorts included ECLIPSE (1764 cases with > 10 pack-years smoking), COPDGene (2797 subjects with > 10 pack-years smoking), NETT (364 subjects > 5 pack-years smoking), and GenKOLs (864 cases with > 2.5 pack-years smoking). We performed an additional analysis in over 700 African Americans from the COPDGene study. Pre-and post-bronchodilator spirometry was performed on all subjects. BDR was calculated in response to administered albuterol as absolute change in FEV1 (BDRABS), change as percentage of predicted FEV1 (BDRPRED), and change as percentage of baseline FEV1 (BDRBASE). Genotyping was performed using Illumina SNP arrays. Additional genotypes were imputed using the 1000 Genomes reference panel. Linear regression was performed in all cohorts, for all three outcomes, adjusting for age and pack-years smoking. We then performed a meta-analysis of results from the four cohorts using a random-effects model to investigate the top SNPs from each outcome. SNPs were filtered for minor allele frequency > 0.01. Results Over 6.3 million unique SNPs from 5789 COPD subjects (GOLD stage II or higher) were investigated. In a meta-analysis, SNPs in HS6ST3 (P=1.7x10-8) were associated with BDRBLINE, SNPs in XKR4 were associated with BDRPRED (P=5.8x10-8) and BDRBLINE (P=1.3x10-7), and SNPs in the CUBN gene were associated with BDRABS (P=2.6x10-7) and BDRPRED (P=7.0x10-7). Among African American subjects, SNPs in CDH13 were significantly associated with BDRABS (P=1x10-11). Conclusions: Bronchodilator responsiveness in COPD is an important measure of lung function that is likely to have multiple genetic determinants. In a meta-analysis including four case-control cohorts of COPD, we identified several novel variants associated with bronchodilator responsiveness.

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