A genome-wide analysis of the response to inhaled beta2-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. ReganB.J. Make, J.E. Hokanson, J.D. Crapo, T.H. Beaty, C.P. Hersh

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Short-acting beta2-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 beta2-agonists. We combined results in a meta-analysis. In the meta-analysis, single-nucleotide polymorphisms (SNPs) in the genes KCNK1 (P=2.02 x 10-7) and KCNJ2 (P=1.79 x 10-7) were the top associations with BDR. Among African Americans, SNPs in CDH13 were significantly associated with BDR (P=5.1 x 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.
Original languageEnglish
Pages (from-to) 326–335
Number of pages10
JournalPharmacogenomics Journal
Volume16
Issue number4
Early online date27 Oct 2015
DOIs
Publication statusPublished - Aug 2016

Keywords

  • RECTIFIER K+ CURRENT
  • SMOOTH-MUSCLE-CELLS
  • LARGE GENE LISTS
  • BRONCHODILATOR RESPONSIVENESS
  • SUSCEPTIBILITY LOCUS
  • ADRB2 POLYMORPHISMS
  • ASSOCIATION
  • COPD
  • VARIANTS
  • CHANNELS

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