A genome-wide analysis of the response to inhaled β2-agonists in chronic obstructive pulmonary disease.
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.
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.
M
M
Hardin
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.
M H
MH
Cho
Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
M-L
ML
McDonald
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.
E
E
Wan
Wolfson Institute for Biomedical Research, University College London, London, UK.
D A
DA
Lomas
UBC Department of Radiology, Vancouver General Hospital, Vancouver, Canada.
H O
HO
Coxson
Centre for Inflammation Research, University of Edinburgh, Edinburgh, Scotland, UK.
W
W
MacNee
Department of Respiratory Medicine, Manchester Academic Health Sciences Centre, University Hospital of South Manchester, Manchester, UK.
J
J
Vestbo
GlaxoSmithKline, Research Triangle Park, NC, USA.
J C
JC
Yates
Thorax Institute, Hospital Clinic, IDIBAPS, Univ Barcelona and CIBERES, Barcelona, Spain.
A
A
Agusti
Department of Pulmonary and Rehabilitation Medicine, University of Liverpool, Liverpool, UK.
P M A
PM
Calverley
Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
B
B
Celli
GlaxoSmithKline, Research Triangle Park, NC, USA.
C
C
Crim
Pulmonary and Critical Care Division, Department of Medicine, University of Nebraska, Omaha, NE, USA.
S
S
Rennard
Center for Chronic Diseases, University Hospital Maastricht, Maastricht, The Netherlands.
E
E
Wouters
Department of Clinical Science, University of Bergen, Bergen, Norway.
P
P
Bakke
Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama, Birmingham, AL, USA.
S P
SP
Bhatt
Division of Pulmonary and Critical Care, Temple University Hospital, Philadelphia, PA, USA.
V
V
Kim
University of California, San Diego, San Diego, CA, USA.
J
J
Ramsdell
Division of Pulmonary Sciences and Critical Care Medicine, National Jewish Health, Denver, CO, USA.
E A
EA
Regan
Division of Pulmonary Sciences and Critical Care Medicine, National Jewish Health, Denver, CO, USA.
B J
BJ
Make
Department of Epidemiology, Colorado School of Public Health, University of Colorado Denver, Denver, CO, USA.
J E
JE
Hokanson
Division of Pulmonary Sciences and Critical Care Medicine, National Jewish Health, Denver, CO, USA.
J D
JD
Crapo
Johns Hopkins School of Public Health, Baltimore, MD, USA.
T H
TH
Beaty
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.
C P
CP
Hersh
D058666:Adrenergic beta-2 Receptor Agonists / Q000627:therapeutic use*; D001741:Black or African American / Q000235:genetics; D000368:Aged; D001993:Bronchodilator Agents / Q000627:therapeutic use*; D015820:Cadherins / Q000235:genetics; D005060:Europe; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008168:Lung / Q000187:drug effects* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D009520:New Zealand; D009656:North America; D000071185:Pharmacogenomic Testing; D000071184:Pharmacogenomic Variants / Q000235:genetics*; D010641:Phenotype; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics; D024683:Potassium Channels, Tandem Pore Domain / Q000235:genetics; D029424:Pulmonary Disease, Chronic Obstructive / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics* / Q000503:physiopathology; D012307:Risk Factors; D049031:Sarcoglycans / Q000235:genetics; D012720:Severity of Illness Index; D013147:Spirometry; D016896:Treatment Outcome; D044465:White People / Q000235:genetics
D058666:Adrenergic beta-2 Receptor Agonists; D001993:Bronchodilator Agents; D015820:Cadherins; C099972:H-cadherin; C489457:KCNJ2 protein, human; C109137:KCNK1 protein, human; D024661:Potassium Channels, Inwardly Rectifying; D024683:Potassium Channels, Tandem Pore Domain; C526570:SGCD protein, human; D049031:Sarcoglycans