Published ahead of print on July 10, 2008, doi:10.1164/rccm.200709-1363OC
© 2008 American Thoracic Society doi: 10.1164/rccm.200709-1363OC
ARG1 Is a Novel Bronchodilator Response GeneScreening and Replication in Four Asthma Cohorts1 Channing Laboratory, and 2 Pulmonary Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; 3 Center for Genomic Medicine, Brigham and Women's Hospital, Boston, Massachusetts; 4 Harvard School of Public Health, Boston, Massachusetts; 5 Department of Mathematics and Statistics, Utah State University, Logan, Utah; 6 Nemours Children's Clinic, Centers for Clinical Pediatric Pharmacology and Pharmacogenetics, Jacksonville, Florida; 7 Vermont Lung Center, Department of Medicine and Physiology, University of Vermont, Burlington, Vermont; 8 Center for Human Genomics, Section of Pulmonary, Critical Care, Allergy and Immunologic Diseases, Wake Forest University School of Medicine, Winston-Salem, North Carolina; 9 Pulmonary Clinical Research, Sepracor, Inc., Marlborough, Massachusetts; and 10 Cardiopulmonary Genomics Program, University of Maryland School of Medicine, Baltimore, Maryland Correspondence and requests for reprints should be addressed to Augusto A. Litonjua, M.D., M.P.H., Channing Laboratory, 181 Longwood Avenue, Boston, MA 02115. E-mail: augusto.litonjua{at}channing.harvard.edu Rationale: Inhaled β-agonists are one of the most widely used classes of drugs for the treatment of asthma. However, a substantial proportion of patients with asthma do not have a favorable response to these drugs, and identifying genetic determinants of drug response may aid in tailoring treatment for individual patients. Objectives: To screen variants in candidate genes in the steroid and β-adrenergic pathways for association with response to inhaled β-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 β-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. Measurements and Main Results: We identified 17 genes from the screening algorithm and genotyped 99 SNPs from these genes in a second population of patients with asthma. We then genotyped 63 SNPs from four genes with significant associations with BDR, for replication in a third and fourth population of patients with asthma. Evidence for association from the four 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). Conclusions: These findings identify ARG1 as a novel gene for acute BDR in both children and adults with asthma.
Key Words: pharmacogenetics • asthma • bronchodilator agents
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