@article{7b44581393814e1f8594c08c0784d0f0,
title = "A genome-wide association study of bronchodilator response in participants of European and African ancestry from six independent cohorts",
abstract = "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.",
author = "Gereige, {Jessica D.} and Hanfei Xu and Ortega, {Victor E.} and Cho, {Michael H.} and Ming Liu and Phuwanat Sakornsakolpat and Silverman, {Edwin K.} and Beaty, {Terri H.} and Miller, {Bruce E.} and Per Bakke and Amund Gulsvik and Hersh, {Craig P.} and Morrow, {Jarrett D.} and Ampleford, {Elizabeth J.} and Hawkins, {Gregory A.} and Bleecker, {Eugene R.} and Meyers, {Deborah A.} and Peters, {Stephen P.} and Celed{\'o}n, {Juan C.} and Kelan Tantisira and Jiang Li and Jos{\'e}e Dupuis and O{\textquoteright}connor, {George T.}",
note = "Funding Information: Support statement: This work was supported by the National Institutes of Health (NIH) through a Ruth L. Kirschstein National Research Service Award 5T32HL007035 ( J.D. Gereige), R01 HL142992 (V.E. Ortega), NIH U01 HL65899 and NIH R01 HL127332 (K. Tantisira), NIH R01HL130512 (C.P. Hersh), R01HL149861, R01HL137927, R01 HL089856, and R01HL147148 (M.H. Cho). The Framingham Heart Study is conducted and supported by the NHLBI in collaboration with Boston University (contract numbers N01-HC-25195, HHSN268201500001I and 75N92019D00031). SPIROMICS was supported by U01 HL137880 and contracts from the NHLBI (HHSN268200900013C, HHSN268200900014C, HHSN268200900015C, HHSN268200900016C, HHSN268200900017C, HHSN268200900018C, HHSN268200900019C and HHSN268200900020C), which were supplemented by contributions made through the Foundation for the NIH from AstraZeneca; Bellerophon Therapeutics; Boehringer-Ingelheim Pharmaceuticals, Inc.; Chiesi Farmaceutici SpA; Forest Research Institute, Inc.; GlaxoSmithKline (GSK); Grifols Therapeutics, Inc.; Ikaria, Inc.; Nycomed GmbH; Takeda Pharmaceutical Company; Novartis Pharmaceuticals Corporation; Regeneron Pharmaceuticals, Inc.; and Sanofi. COPDGene was supported by Award Number U01 HL089897 and Award Number U01 HL089856 from the NHLBI. COPDGene is also supported by the COPD Foundation through contributions made to an Industry Advisory Board that has included AstraZeneca, Bayer Pharmaceuticals, Boehringer-Ingelheim, Genentech, GSK, Novartis, Pfizer and Sunovion. ECLIPSE and GenKOLS were supported by GSK. TESRA was supported by Roche. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NHLBI or the NIH. Funding information for this article has been deposited with the Crossref Funder Registry. Funding Information: Acknowledgements: The Genotype Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, National Heart, Lung, and Blood Institute (NHLBI), NIDA, NIMH and NINDS. The data used for the analyses described in this manuscript were obtained from the GTEx Portal on 7 August 2020. We would like to acknowledge Achilleas Pitsillides for the help and support he provided in the use of GTEx. The authors also acknowledge the patients, families, recruiters, healthcare providers and community clinics for their participation in FHS, COPDGene, ECLIPSE, TESRA, GenKOLS, SPIROMICS, GACRS and CAMP. Publisher Copyright: {\textcopyright} The authors 2022.",
year = "2022",
month = apr,
day = "1",
doi = "10.1183/23120541.00484-2021",
language = "English (US)",
volume = "8",
journal = "ERJ Open Research",
issn = "2312-0541",
publisher = "European Respiratory Society",
number = "2",
}