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Pharmacogenomics J. 2014 Feb;14(1):41-7. doi: 10.1038/tpj.2013.5. Epub 2013 Mar 19.

A genome-wide association study of bronchodilator response in asthmatics.

Author information

1
Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
2
1] Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA [2] Center for Genomic Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
3
1] Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA [2] Pulmonary Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
4
Novartis, Cambridge, MA, USA.
5
Vermont Lung Center, Department of Medicine and Physiology, University of Vermont, Burlington, Vermont, USA.
6
Center for Genomics and Personalized Medicine Research, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
7
Pulmatrix, Lexington, MA, USA.
8
Nemours Children's Clinic, Centers for Clinical Pediatric Pharmacology and Pharmacogenetics, Jacksonville, FL, USA.
9
Arizona Respiratory Center and BIO5 Institute, University of Arizona, Tucson, AZ, USA.
10
Department of Public Health Sciences, Pennsylvania State University, Hershey, PA, USA.
11
Hospital Nacional de Niños, San José, Costa Rica.
12
Division of Pediatric Pulmonary Medicine, Allergy and Immunology, Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA.
13
Harvard School of Public Health, Boston, MA, USA.
14
1] Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA [2] Center for Genomic Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA [3] Pulmonary Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA [4] Harvard School of Public Health, Boston, MA, USA.

Abstract

Reversibility of airway obstruction in response to β2-agonists is highly variable among asthmatics, which is partially attributed to genetic factors. In a genome-wide association study of acute bronchodilator response (BDR) to inhaled albuterol, 534 290 single-nucleotide polymorphisms (SNPs) were tested in 403 white trios from the Childhood Asthma Management Program using five statistical models to determine the most robust genetic associations. The primary replication phase included 1397 polymorphisms in three asthma trials (pooled n=764). The second replication phase tested 13 SNPs in three additional asthma populations (n=241, n=215 and n=592). An intergenic SNP on chromosome 10, rs11252394, proximal to several excellent biological candidates, significantly replicated (P=1.98 × 10(-7)) in the primary replication trials. An intronic SNP (rs6988229) in the collagen (COL22A1) locus also provided strong replication signals (P=8.51 × 10(-6)). This study applied a robust approach for testing the genetic basis of BDR and identified novel loci associated with this drug response in asthmatics.

PMID:
23508266
PMCID:
PMC3706515
DOI:
10.1038/tpj.2013.5
[Indexed for MEDLINE]
Free PMC Article

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