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A genome-wide association study of bronchodilator response in asthmatics

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.

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Acknowledgements

This work was supported by U01 HL65899 and P01 HL083069 from the National Heart, Lung and Blood Institute (NHLBI). We thank all families for their enthusiastic participation in the CAMP Genetics Ancillary Study and the CAMP investigators and research teams, who were supported by the NHLBI N01 HR16049. Additional support for this research came from NHLBI grants N01 HR16044, HR16045, HR16046, HR16047, HR16048, HR16049, HR16050, HR16051 and HR16052. All data collection from the CAMP Genetic Ancillary Study was conducted at the Channing Laboratory of the Brigham and Women’s Hospital under appropriate CAMP policies and human subject’s protections. The CAMP Genetics Ancillary Study is supported by U01 HL075419, U01 HL65899, P01 HL083069, R01 HL086601 and T32 HL07427 from the NIH/NHLBI. Collection of microarray data from immortalized lymphoblastoid cell lines of CAMP subjects was supported by K23 HG003983 and R01 HL092197 from the NIH/NHGRI. We acknowledge the American Lung Association (ALA) and the ALA’s Asthma Clinical Research Centers investigators and research teams for use of LOCCS and LODO data, with additional funding from HL071394 and HL074755 from the NHLBI, and Nemours Children's’ Clinic. GlaxoSmithKline supported the conduct of the LOCCS Trial by an unrestricted grant to the ALA. We acknowledge Sepracor for the use of the Asthma Trial data. The Single-Nucleotide Polymorphism Health Association Asthma Resource Project (SHARP) was funded by grants from the NHLBI U01 HL51510, U01 HL51834, U01 HL51831, U01 HL51845, U01 HL51843, M01 RR00079 and M01 RR03186, and was carried out by researchers from the Asthma Clinical Research Network (ACRN), CAMP and Childhood Asthma Research and Education (CARE) Network. Details are available in the Online Repository and on the dbGaP (database of Genotypes and Phenotypes) website: www.ncbi.nlm.nih.gov/sites/entrez?Db=gap. The GACRS was supported by HL04370 and HL66289 from the NIH.

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Duan, Q., Lasky-Su, J., Himes, B. et al. A genome-wide association study of bronchodilator response in asthmatics. Pharmacogenomics J 14, 41–47 (2014). https://doi.org/10.1038/tpj.2013.5

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