title: Genome-wide association study of short-acting β2-agonists. A novel genome-wide significant locus on chromosome 2 near ASB3.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  To investigate whether a genome-wide association study (GWAS) could identify novel pharmacogenetic loci in asthma.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: 1 Division of Pulmonary and Critical Care Medicine and.
authors.forename: Elliot
authors.initials: E
authors.lastname: Israel
authors.forename: Jessica
authors.initials: J
authors.lastname: Lasky-Su
authors.forename: Amy
authors.initials: A
authors.lastname: Markezich
authors.forename: Amy
authors.initials: A
authors.lastname: Damask
authors.forename: Stanley J
authors.initials: SJ
authors.lastname: Szefler
authors.forename: Brooke
authors.initials: B
authors.lastname: Schuemann
authors.forename: Barbara
authors.initials: B
authors.lastname: Klanderman
authors.forename: Jody
authors.initials: J
authors.lastname: Sylvia
authors.forename: Shamsah
authors.initials: S
authors.lastname: Kazani
authors.forename: Rongling
authors.initials: R
authors.lastname: Wu
authors.forename: Fernando
authors.initials: F
authors.lastname: Martinez
authors.forename: Homer A
authors.initials: HA
authors.lastname: Boushey
authors.forename: Vernon M
authors.initials: VM
authors.lastname: Chinchilli
authors.forename: Dave
authors.initials: D
authors.lastname: Mauger
authors.forename: Scott T
authors.initials: ST
authors.lastname: Weiss
authors.forename: Kelan G
authors.initials: KG
authors.lastname: Tantisira
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists; D017089:Ankyrin Repeat / Q000235:genetics*; D001249:Asthma / Q000188:drug therapy* / Q000235:genetics*; D001993:Bronchodilator Agents; D002648:Child; D002675:Child, Preschool; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D055106:Genome-Wide Association Study; D060005:Genotyping Techniques; D006801:Humans; D008297:Male; D009130:Muscle, Smooth / Q000502:physiology; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics; D015656:Respiratory Mechanics / Q000235:genetics*; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics*
chemical_list: C553443:ADRB2 protein, human; C502210:ASB3 protein, human; D058666:Adrenergic beta-2 Receptor Agonists; D001993:Bronchodilator Agents; D018343:Receptors, Adrenergic, beta-2; D050826:Suppressor of Cytokine Signaling Proteins
keywords: bronchodilator; genotype; single-nucleotide polymorphism