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

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

doi:10.1038/tpj.2015.65

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

Journal article

Peer reviewed

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

M Hardin, M H Cho, M-L McDonald, E Wan, D A Lomas, H O Coxson, W MacNee, J Vestbo, J C Yates, A Agusti, …

The pharmacogenomics journal, Vol.16(4), pp.326-335

08/2016

DOI: 10.1038/tpj.2015.65

PMCID: PMC4848212

PMID: 26503814

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http://nrs.harvard.edu/urn-3:HUL.InstRepos:29002591View

Open Access

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.

Europe

New Zealand

North America

Phenotype

Bronchodilator Agents - therapeutic use

Spirometry

Humans

Middle Aged

Male

Pulmonary Disease, Chronic Obstructive - physiopathology

Adrenergic beta-2 Receptor Agonists - therapeutic use

Female

Cadherins - genetics

Pharmacogenomic Variants - genetics

Pulmonary Disease, Chronic Obstructive - genetics

Severity of Illness Index

Pulmonary Disease, Chronic Obstructive - diagnosis

European Continental Ancestry Group - genetics

Genome-Wide Association Study

Risk Factors

African Americans - genetics

Potassium Channels, Tandem Pore Domain - genetics

Genotype

Potassium Channels, Inwardly Rectifying - genetics

Treatment Outcome

Lung - physiopathology

Pharmacogenomic Testing

Sarcoglycans - genetics

Lung - drug effects

Aged

Pulmonary Disease, Chronic Obstructive - drug therapy

Details

Title: Subtitle: A genome-wide analysis of the response to inhaled β2-agonists in chronic obstructive pulmonary disease
Creators: M Hardin - Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
M H Cho - Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
M-L McDonald - Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
E Wan - Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
D A Lomas - Wolfson Institute for Biomedical Research, University College London, London, UK
H O Coxson - UBC Department of Radiology, Vancouver General Hospital, Vancouver, Canada
W MacNee - Centre for Inflammation Research, University of Edinburgh, Edinburgh, Scotland, UK
J Vestbo - Department of Respiratory Medicine, Manchester Academic Health Sciences Centre, University Hospital of South Manchester, Manchester, UK
J C Yates - GlaxoSmithKline, Research Triangle Park, NC, USA
A Agusti - Thorax Institute, Hospital Clinic, IDIBAPS, Univ Barcelona and CIBERES, Barcelona, Spain
P M A Calverley - Department of Pulmonary and Rehabilitation Medicine, University of Liverpool, Liverpool, UK
B Celli - Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
C Crim - GlaxoSmithKline, Research Triangle Park, NC, USA
S Rennard - Pulmonary and Critical Care Division, Department of Medicine, University of Nebraska, Omaha, NE, USA
E Wouters - Center for Chronic Diseases, University Hospital Maastricht, Maastricht, The Netherlands
P Bakke - Department of Clinical Science, University of Bergen, Bergen, Norway
S P Bhatt - Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama, Birmingham, AL, USA
V Kim - Division of Pulmonary and Critical Care, Temple University Hospital, Philadelphia, PA, USA
J Ramsdell - University of California, San Diego, San Diego, CA, USA
E A Regan - Division of Pulmonary Sciences and Critical Care Medicine, National Jewish Health, Denver, CO, USA
B J Make - Division of Pulmonary Sciences and Critical Care Medicine, National Jewish Health, Denver, CO, USA
J E Hokanson - Department of Epidemiology, Colorado School of Public Health, University of Colorado Denver, Denver, CO, USA
J D Crapo - Division of Pulmonary Sciences and Critical Care Medicine, National Jewish Health, Denver, CO, USA
T H Beaty - Johns Hopkins School of Public Health, Baltimore, MD, USA
C P Hersh - Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
ECLIPSE Investigators
COPDGene Investigators
COPDGene Investigators—clinical centers
Contributors: Eric A Hoffman (Contributor) - University of Iowa, Radiology
Resource Type: Journal article
Publication Details: The pharmacogenomics journal, Vol.16(4), pp.326-335
DOI: 10.1038/tpj.2015.65
PMID: 26503814
PMCID: PMC4848212
NLM abbreviation: Pharmacogenomics J
ISSN: 1470-269X
eISSN: 1473-1150
Publisher: United States
Grant note: P30 ES005605 / NIEHS NIH HHS U01 HL089856 / NHLBI NIH HHS P01 HL083069 / NHLBI NIH HHS R01 NR013377 / NINR NIH HHS U01 HL089897 / NHLBI NIH HHS R01 HL089856 / NHLBI NIH HHS P01 HL105339 / NHLBI NIH HHS MR/N024842/1 / Medical Research Council R01 HL089897 / NHLBI NIH HHS R01 HL094635 / NHLBI NIH HHS K12 HL089990 / NHLBI NIH HHS K12 HL120004 / NHLBI NIH HHS
Language: English
Date published: 08/2016
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Radiology; Internal Medicine
Record Identifier: 9984051882802771

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