A genome-wide association study of bronchodilator response in participants of European and African ancestry from six independent cohorts
Year: 2022
Type: article
Study design: Observational Study
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<5×10−6to identify suggestive variants of interest, we identified three SNPs with possible biological relevance: rs35870000 (withinFREM1), which may be involved in IgE- and IL5-induced changes in airway smooth muscle cell responsiveness; rs10426116 (withinZNF284), a zinc finger protein, which has been implicated in asthma and BDR previously; and rs4782614 (nearATP2C2), 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.
Source: ERJ Open Research
Authors: Jessica D. Gereige, Hanfei Xu, Victor E. Ortega, Michael H. Cho, Ming Liu, Phuwanat Sakornsakolpat, Edwin K. Silverman, Terri H. Beaty, Bruce E. Miller, Per Bakke, Amund Gulsvik, Craig P. Hersh, Jarrett D. Morrow, Elizabeth J. Ampleford, Gregory A. Hawkins, Eugene R. Bleecker, Deborah A. Meyers, Stephen P. Peters, Juan C. Celedón, Kelan Tantisira, Jiang Li, Josée Dupuis, George T. O'Connor
Institutions: Boston University, Boston Medical Center, University of Arizona, Brigham and Women's Hospital, Harvard University, Worcester Polytechnic Institute, Johns Hopkins University, GlaxoSmithKline (United States), University of Bergen, University of Pittsburgh, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, University of California San Diego, Rady Children's Hospital-San Diego, The Seventh Affiliated Hospital of Sun Yat-sen University
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $808
Funders: Boehringer Ingelheim, Pfizer, AstraZeneca, GlaxoSmithKline, Roche, Sanofi, Ikaria, Chiesi Farmaceutici, COPD Foundation, Novartis Pharmaceuticals Corporation, Takeda Pharmaceutical Company, Sunovion, Regeneron Pharmaceuticals, Bellerophon Therapeutics, Forest Research Institute, Bayer HealthCare, Grifols, National Institutes of Health, Genentech, National Heart, Lung, and Blood Institute, National Institute of Mental Health, National Institute on Drug Abuse, National Human Genome Research Institute, NIH Office of the Director, National Cancer Institute, National Institute of Neurological Disorders and Stroke, Common Fund
Awards: Pharmacogenetics of Asthma Treatment, G2099663897, G2212190077, G250621538, G278200998, G3027037974, Identifying functional variants in COPD GWAS loci, G3405256882, Genetic and Functional Dissection of a Cluster of COPD GWAS Signals on Chromosome 4q, G3868091120, G3999916299, Effects of Rare Variants and Ancestry on Beta Agonist Response in Asthma and COPD, (2 of 2) Genetic Epidemiology of COPD, MICRORNAS IN CIRCULATION: ONTOLOGIES OF ASTHMA SEVERITY AND TREATMENT (MICROCOAST), G4749522346, G4976486911, G5164707915, (2 of 2) Genetic Epidemiology of COPD, The Framingham Heart Study, (1 of 2) Genetic Epidemiology of COPD, SYSTEMS GENOMICS OF THE ASTHMA-COPD OVERLAP SYNDROME, G7206313631, SPIROMICS II: Biological underpinnings of COPD heterogeneity and progression, Clinical Implications, Genomics, and Transcriptions of Mucus Plugging in Smokers, Integrative omics pipeline to identify novel COPD genes and pathways, G8957911378, G9000273487, Biology of the Lung: A Multidisciplinary Program, G9000296006, Leveraging Pharmacogenomics in Asthma for Predication, Mechanism and Endotyping
OpenAlex ID: W4283397944