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. Regan; B.J. Make; J.E. Hokanson; J.D. Crapo; T.H. Beaty; C.P. Hersh

doi:10.1038/tpj.2015.65

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

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-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 language	English
Pages (from-to)	326–335
Number of pages	10
Journal	Pharmacogenomics Journal
Volume	16
Issue number	4
Early online date	27 Oct 2015
DOIs	https://doi.org/10.1038/tpj.2015.65
Publication status	Published - 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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Cite this

Hardin, M., Cho, M. H., McDonald, M. L., Wan, E., Lomas, D. A., Coxson, H. O., MacNee, W., Vestbo, J., Yates, J. C., Agusti, A., Calverley, P. M. A., Celli, B., Crim, C., Rennard, S., Wouters, E., Bakke, P., Bhatt, S. P., Kim, V., Ramsdell, J., ... Hersh, C. P. (2016). A genome-wide analysis of the response to inhaled beta2-agonists in chronic obstructive pulmonary disease. Pharmacogenomics Journal, 16(4), 326–335. https://doi.org/10.1038/tpj.2015.65

@article{4d8d8937551f4835a1989d095c5a32d1,

title = "A genome-wide analysis of the response to inhaled beta2-agonists in chronic obstructive pulmonary disease",

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.",

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

author = "M. Hardin and M.H. Cho and M.L. McDonald and E. Wan and D.A. Lomas and H.O. Coxson and W. MacNee and J. Vestbo and J.C. Yates and A. Agusti and P.M.A. Calverley and B. Celli and C. Crim and S. Rennard and E. Wouters and P. Bakke and S.P. Bhatt and V. Kim and J. Ramsdell and E.A. Regan and B.J. Make and J.E. Hokanson and J.D. Crapo and T.H. Beaty and C.P. Hersh",

year = "2016",

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doi = "10.1038/tpj.2015.65",

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volume = "16",

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Hardin, M, Cho, MH, McDonald, ML, Wan, E, Lomas, DA, Coxson, HO, MacNee, W, Vestbo, J, Yates, JC, Agusti, A, Calverley, PMA, Celli, B, Crim, C, Rennard, S, Wouters, E, Bakke, P, Bhatt, SP, Kim, V, Ramsdell, J, Regan, EA, Make, BJ, Hokanson, JE, Crapo, JD, Beaty, TH & Hersh, CP 2016, 'A genome-wide analysis of the response to inhaled beta2-agonists in chronic obstructive pulmonary disease', Pharmacogenomics Journal, vol. 16, no. 4, pp. 326–335. https://doi.org/10.1038/tpj.2015.65

TY - JOUR

T1 - A genome-wide analysis of the response to inhaled beta2-agonists in chronic obstructive pulmonary disease

AU - Hardin, M.

AU - Cho, M.H.

AU - McDonald, M.L.

AU - Wan, E.

AU - Lomas, D.A.

AU - Coxson, H.O.

AU - MacNee, W.

AU - Vestbo, J.

AU - Yates, J.C.

AU - Agusti, A.

AU - Calverley, P.M.A.

AU - Celli, B.

AU - Crim, C.

AU - Rennard, S.

AU - Wouters, E.

AU - Bakke, P.

AU - Bhatt, S.P.

AU - Kim, V.

AU - Ramsdell, J.

AU - Regan, E.A.

AU - Make, B.J.

AU - Hokanson, J.E.

AU - Crapo, J.D.

AU - Beaty, T.H.

AU - Hersh, C.P.

PY - 2016/8

Y1 - 2016/8

N2 - 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.

AB - 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.

KW - RECTIFIER K+ CURRENT

KW - SMOOTH-MUSCLE-CELLS

KW - LARGE GENE LISTS

KW - BRONCHODILATOR RESPONSIVENESS

KW - SUSCEPTIBILITY LOCUS

KW - ADRB2 POLYMORPHISMS

KW - ASSOCIATION

KW - COPD

KW - VARIANTS

KW - CHANNELS

U2 - 10.1038/tpj.2015.65

DO - 10.1038/tpj.2015.65

M3 - Article

SN - 1470-269X

VL - 16

SP - 326

EP - 335

JO - Pharmacogenomics Journal

JF - Pharmacogenomics Journal

IS - 4

ER -