A genome-wide association study of bronchodilator response in participants of European and African ancestry from six independent cohorts.

Introduction: Bronchodilator response (BDR) is a measurement of acute bronchodilation in response to short-acting β2-agonists, with a heritability between 10 and 40%. Identifying genetic variants associated with BDR may lead to a better understanding of its complex pathophysiology.
Methods: We performed a genome-wide association study (GWAS) of BDR in six adult cohorts with participants of European ancestry (EA) and African ancestry (AA) including community cohorts and cohorts ascertained on the basis of obstructive pulmonary disease. Validation analysis was carried out in two paediatric asthma cohorts.
Results: A total of 10 623 EA and 3597 AA participants were included in the analyses. No single nucleotide polymorphism (SNP) was associated with BDR at the conventional genome-wide significance threshold (p<5×10 ^-8 ). Performing fine mapping and using a threshold of p<5×10 ^-6 to identify suggestive variants of interest, we identified three SNPs with possible biological relevance: rs35870000 (within FREM1 ), which may be involved in IgE- and IL5-induced changes in airway smooth muscle cell responsiveness; rs10426116 (within ZNF284 ), a zinc finger protein, which has been implicated in asthma and BDR previously; and rs4782614 (near ATP2C2 ), involved in calcium transmembrane transport. Validation in paediatric cohorts yielded no significant SNPs, possibly due to age-genotype interaction effects.
Conclusion: Ancestry-stratified and ancestry-combined GWAS meta-analyses of over 14 000 participants did not identify genetic variants associated with BDR at the genome-wide significance threshold, although a less stringent threshold identified three variants showing suggestive evidence of association. A common definition and protocol for measuring BDR in research may improve future efforts to identify variants associated with BDR.
Competing Interests: Conflict of interest: J.D. Gereige reports that support for the present manuscript received from NIH; grants or contracts from NIH, outside the submitted work; and support for attending meetings received from ACAAI, outside the submitted work. Conflict of interest: H. Xu reports that support for the present manuscript received from NIH. Conflict of interest: V.E. Ortega reports that support for the present manuscript received from NHLBI; AstraZeneca; Bellerophon Therapeutics; Boehringer-Ingelheim Pharmaceuticals, Inc.; Chiesi Farmaceutici SpA; Forest Research Institute, Inc.; GSK; Grifols Therapeutics, Inc.; Ikaria, Inc.; Nycomed GmbH; Takeda Pharmaceutical Company; Novartis Pharmaceuticals Corporation; Regeneron Pharmaceuticals, Inc; and Sanofi. Consulting fees received from Sanofi and Regeneron, outside the submitted work. Conflict of interest: M.H. Cho reports that support for the present manuscript has been received from NHLBI; grants or contracts received from Bayer and GSK, outside the submitted work; consulting fees received from AstraZeneca and Genentech, outside the submitted work; and payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events received from Illumina, outside the submitted work. Conflict of interest: E.K. Silverman reports that support for the present manuscript received from NIH; and grants or contracts received from Bayer and GlaxoSmithKline, outside the submitted work. Conflict of interest: C.P. Hersh reports that support for the present manuscript has been received from National Institutes of Health; grants or contracts received from Bayer, Boehringer-Ingelheim, Novartis, Vertex and Alpha-1 Foundation, outside the submitted work; and consulting fees received from Takeda, outside the submitted work. Conflict of interest: J.D. Morrow reports that support for the present manuscript received from NIH NHLBI. Conflict of interest: B.E. Miller is a shareholder at GSK; disclosure made outside the submitted work. Conflict of interest: P. Bakke reports receiving payment for lectures from GlaxoSmithKline, Boehringer-Ingelheim, Novartis and AstraZeneca, outside the submitted work; and an advisory Board fee received from AstraZeneca, outside the submitted work. Conflict of interest: E.R. Bleecker reports receiving grants or contracts from AstraZeneca, Novartis, Regeneron and Sanofi Genzyme, outside the submitted work; consulting fees received from ALK-Abello, AstraZeneca, Glaxo Smith Kline, Knopp Pharmaceuticals, Novartis, Regeneron and Sanofi Genzyme, outside the submitted work; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from ALK-Abello, AstraZeneca and GlaxoSmithKline, outside the submitted work; and support for attending meetings and/or travel received from ALK-Abello, AstraZeneca, GlaxoSmithKline, Novartis, Regeneron and Sanofi Genzyme, outside the submitted work. The following companies provided financial support for the NHLBI SARP study activities at the Coordinating and Clinical Centers: AstraZeneca, Boehringer-Ingelheim, Genentech, Sanofi-Genzyme-Regeneron, and TEVA; these companies had no role in study design or data analysis, and the only restriction on the funds was that they be used to support the SARP initiative. Conflict of interest: S.P Peters reports that support for the present manuscript received from NHLBI; AstraZeneca; Bellerophon Therapeutics; Boehringer-Ingelheim Pharmaceuticals, Inc.; Chiesi Farmaceutici SpA; Forest Research Institute, Inc.; GSK; Grifols Therapeutics, Inc.; Ikaria, Inc.; Nycomed GmbH; Takeda Pharmaceutical Company; Novartis Pharmaceuticals Corporation; Regeneron Pharmaceuticals, Inc.; and Sanofi. Consulting fees received from NIAID, GSK, Syneos, and Parexel, outside the submitted work. Conflict of interest: K. Tantisira reports grants or contracts received from National Institutes of Health, outside the submitted work. Conflict of interest: J. Li reports that support for the present manuscript received from NIH. Conflict of interest: J. Dupuis reports that support for the present manuscript received from NIH/NHLBI Framingham Heart Study contract. Conflict of interest: G.T. O'Connor reports that support for the present manuscript received from NIH and grants or contracts received from NIH outside the submitted work.
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