Genome-wide association study of short-acting β2-agonists. A novel genome-wide significant locus on chromosome 2 near ASB3

• Published in: American journal of respiratory and critical care medicine Vol. 191; no. 5; pp. 530 - 537
• Main Authors: Israel, Elliot, Lasky-Su, Jessica, Markezich, Amy, Damask, Amy, Szefler, Stanley J, Schuemann, Brooke, Klanderman, Barbara, Sylvia, Jody, Kazani, Shamsah, Wu, Rongling, Martinez, Fernando, Boushey, Homer A, Chinchilli, Vernon M, Mauger, Dave, Weiss, Scott T, Tantisira, Kelan G
• Format: Journal Article
• Language: English
• Published: United States American Thoracic Society 01.03.2015
• Subjects: Adrenergic beta-2 Receptor Agonists; Ankyrin Repeat - genetics; Asthma - drug therapy; Asthma - genetics; Bronchodilator Agents; Child; Child, Preschool; Chromosomes, Human, Pair 2 - genetics; Female; Gene Frequency; Genome-Wide Association Study; Genotyping Techniques; Humans; Male; Muscle, Smooth - physiology; Original; Phenotype; Polymorphism, Single Nucleotide - genetics; Receptors, Adrenergic, beta-2 - genetics; Respiratory Mechanics - genetics; Suppressor of Cytokine Signaling Proteins - genetics; single-nucleotide polymorphism; bronchodilator; genotype
• ISSN: 1535-4970; 1073-449X; 1535-4970
• DOI: 10.1164/rccm.201408-1426OC

β2-Agonists are the most common form of treatment of asthma, but there is significant variability in response to these medications. A significant proportion of this responsiveness may be heritable. To investigate whether a genome-wide association study (GWAS) could identify novel pharmacogenetic loci in asthma. We performed a GWAS of acute bronchodilator response (BDR) to inhaled β2-agonists. A total of 444,088 single-nucleotide polymorphisms (SNPs) were examined in 724 individuals from the SNP Health Association Resource (SHARe) Asthma Resource Project (SHARP). The top 50 SNPs were carried forward to replication in a population of 444 individuals. The combined P value for four SNPs reached statistical genome-wide significance aftercorrecting for multiple comparisons. Combined P values for rs350729, rs1840321, rs1384918, and rs1319797 were 2.21 × 10(-10), 5.75 × 10(-8), 9.3 × 10(-8), and 3.95 × 10(-8), respectively. The significant variants all map to a novel genetic region on chromosome 2 near the ASB3 gene, a region associated with smooth muscle proliferation. As compared with the wild type, the presence of the minor alleles reduced the degree of BDR by 20% in the original population and by a similar percentage in the confirmatory population. These GWAS findings for BDR in subjects with asthma suggest that a gene associated with smooth muscle proliferation may influence a proportion of the smooth muscle relaxation that occurs in asthma.