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Meta-Analysis
. 2016 Aug;16(4):326-35.
doi: 10.1038/tpj.2015.65. Epub 2015 Oct 27.

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

M Hardin  1   2 , M H Cho  1   2 , M-L McDonald  1 , E Wan  1   2 , D A Lomas  3 , H O Coxson  4 , W MacNee  5 , J Vestbo  6 , J C Yates  7 , A Agusti  8 , P M A Calverley  9 , B Celli  2 , C Crim  7 , S Rennard  10 , E Wouters  11 , P Bakke  12 , S P Bhatt  13 , V Kim  14 , J Ramsdell  15 , E A Regan  16 , B J Make  16 , J E Hokanson  17 , J D Crapo  16 , T H Beaty  18 , C P Hersh  1   2 ; ECLIPSE and COPDGene Investigators; COPDGene Investigators—clinical centers
Collaborators, Affiliations
Meta-Analysis

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

M Hardin et al. Pharmacogenomics J. 2016 Aug.

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.

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Conflict of interest statement

Conflict of Interest:

The following authors report potential conflicts of interest: Dr Michael Cho receives funding from the NIH and the Alpha-1 Foundation; Dr David Lomas has received grant support, honoraria, and consultancy fees from GlaxoSmithKline. He chairs the GSK Respiratory Therapy Area Board; Dr Harvey Coxson has received $4800 in the years 2009 – 2012 for serving on the steering committee for the ECLIPSE project for GSK, he was the co-investigator on two multi-center studies sponsored by GSK and has received travel expenses to attend meetings related to the project. Dr Coxson has three contract service agreements with GSK (including the ECLIPSE study) to quantify the CT scans in subjects with COPD and a service agreement with Spiration Inc to measure changes in lung volume in subjects with severe emphysema. He has received a fee for speaking at a conference and related travel expenses from AstraZeneca (Australia). Dr Coxson was the recipient of a GSK Clinical Scientist Award in 2010; Dr Jørgen Vestbo has received honoraria for consulting and presenting from Almirall, AstraZeneca, Boehringer-Ingelheim, Chiesi, GSK, Novartis and Takeda; Julie Yates is an employee of and owns stock in GlaxoSmithKline; Dr Alvar Agusti has consulted and received honoraria for lecturing at meeting from different pharmaceutical companies commercializing bronchodilators, including GSK, Boheringer-Ingelheim, AstraZeneca, Almirall, Novartis and Chiesi. Dr Celli has worked as a researcher or consultant for the following companies: GSK, Almirall, Novartis, Forrest, Aeris, Boehringer-Ingelheim, Dey, Altana, Pfizer, and Rox. Dr Courtney Crim is an employee of GlaxoSmithKline LLC, the sponsor of the ECLIPSE trial. He holds stock/stock options in GSK as a portion of his compensation as an employee. As it relates to this manuscript, Dr Crim declares no potential conflict of interest; Dr Rennard has had or currently has a number of relationships with companies who provide products and/or services relevant to outpatient management of chronic obstructive pulmonary disease. These relationships include serving as a consultant, advising regarding clinical trials, speaking at continuing medical education programs and performing funded research both at basic and clinical levels. He does not own any stock in any pharmaceutical companies. These companies include: AARC, American Board of Internal Medicine, Able Associates, Align2 Acton, Almirall, APT, AstraZeneca, American Thoracic Society, Beilenson, Boehringer Ingelheim, Chiesi, CIPLA, Clarus Acuity, CME Incite, COPDFoundation, Cory Paeth, CSA, CSL Behring, CTS Carmel, Dailchi Sankyo, Decision Resources, Dunn Group, Easton Associates, Elevation Pharma, FirstWord, Forest, GLG Research, Gilead, Globe Life Sciences, GlaxoSmithKline, Guidepoint, Health Advance, HealthStar, HSC Medical Education, Johnson and Johnson, Leerink Swan, LEK, McKinsey, Medical Knowledge, Medimmune, Merck, Navigant, Novartis, Nycomed, Osterman, Pearl, PeerVoice, Penn Technology, Pennside, Pfizer, Prescott, Pro Ed Communications, PriMed, Pulmatrix, Quadrant, Regeneron, Saatchi and Saatchi, Sankyo, Schering, Schlesinger Associates, Shaw Science, Strategic North, Summer Street Research, Synapse, Takeda, Telecon SC, ThinkEquity; Dr Per Bakke has consulted for Boehringer- Ingelheim and received compensation; Professor Calverley has received funding from the UK MRC and holds an NIHR programme grant. He has been compensated for work on clinical trials steering committees for GSK, Boehringher Ingelheim and Takeda. He has spoken at meetings supported by these companies and by AstraZeneca, Novartis and Almirall. He holds no stock in any relevant concern and has no contacts with the tobacco industry. Dr Victor Kim has nothing to disclose in relationship to this manuscript but has served on an advisory committee for CSA and has participated in clinical trials sponsored by Boehringer Ingelheim, Glaxo-Smith-Kline, and Roche pharmaceuticals. VK is supported by NHLBI K23HL094696-03. Dr Craig Hersh has received consulting fees from Novartis and CSL Behring.

Figures

Figure 1
Figure 1
Manhattan plots for meta-analysis results for each bronchodilator responsiveness outcome
Figure 2
Figure 2
Regional association plot for KCNJ2 variants associated with the outcome BDRABS
See this image and copyright information in PMC

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