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Published ahead of print on July 10, 2008, doi:10.1164/rccm.200709-1363OC

Am. J. Respir. Crit. Care Med., Volume 178, Number 7, October 2008, 688-694

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Submitted on September 13, 2007
Accepted on July 10, 2008

ARG1 is a Novel Bronchodilator Response Gene: Screening and Replication in Four Asthma Cohorts

Augusto A Litonjua1*, Jessica A Lasky-Su2, Kady Schneiter3, Kelan G Tantisira1, Ross Lazarus4, Barbara Klanderman4, John J Lima5, Charles G Irvin6, Stephen P Peters7, John P Hanrahan8, Stephen B Liggett9, Gregory A Hawkins7, Deborah A Meyers7, Eugene R Bleecker7, Christoph Lange10, and Scott T Weiss4

1 Channing Laboratory, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Pulmonary Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Center for Genomic Medicine, Brigham and Women's Hospital, Boston, MA, USA, 2 Channing Laboratory, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Center for Genomic Medicine, Brigham and Women's Hospital, Boston, MA, USA; Harvard School of Public Health, Boston, MA, USA, 3 Department of Mathematics and Statistics, Utah State University, Logan, UT, USA, 4 Channing Laboratory, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Center for Genomic Medicine, Brigham and Women's Hospital, Boston, MA, USA, 5 Centers for Clinical Pediatric Pharmacology and Pharmacogenetics, Nemours Children's Clinic, Jacksonville, FL, USA, 6 Vermont Lung Center, Department of Medicine and Physiology, University of Vermont, Burlington, VT, USA, 7 Center for Human Genomics, Section of Pulmonary, Critical Care, Allergy and Immunologic Diseases, Wake Forest University School of Medicine, Winston Salem, NC, USA, 8 Pulmonary Clinical Research, Sepracor Inc, Marlborough, MA, USA, 9 Cardiopulmonary Genomics Program, University of Maryland School of Medicine, Baltimore, MD, USA, 10 Harvard School of Public Health, Boston, MA, USA

* To whom correspondence should be addressed. E-mail: augusto.litonjua{at}channing.harvard.edu.

Rationale: Inhaled {beta} agonists are one of the most widely used classes of drugs for the treatment of asthma. However, a substantial proportion of asthmatics do not have a favorable response to these drugs, and identifying genetic determinants of drug response may aid in tailoring treatment for individual patients. Objective: To screen variants in candidate genes in the steroid and {beta} adrenergic pathways for association with response to inhaled {beta} agonists. Methods: We genotyped 844 single nucleotide polymorphisms (SNPs) in 111 candidate genes in 209 children and their parents participating in the Childhood Asthma Management Program. We screened the association of these SNPs with acute response to inhaled {beta} agonists (bronchodilator response, BDR) using a novel algorithm implemented in a family-based association test that ranked SNPs in order of statistical power. Genes that had SNPs with median power in the highest quartile were then taken for replication analyses in three other asthma cohorts. Results: We identified 17 genes from the screening algorithm and genotyped 99 SNPs from these genes in a second population of asthmatics. We then genotyped 63 SNPs from 4 genes with significant associations with BDR, for replication in a third and fourth population of asthmatics. Evidence for association from the 4 asthma cohorts was combined, and SNPs from ARG1 were significantly associated with BDR. SNP rs2781659 survived Bonferroni correction for multiple testing (combined p-value = 0.00048, adjusted p-value = 0.047). Conclusion: These findings identify ARG1 as a novel gene for acute BDR in both childhood and adult asthmatics.


Key words: Pharmacogenetics; Asthma; Bronchodilator Agents







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