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

Am J Respir Crit Care Med. 2015 Mar 1;191(5):530-7. doi: 10.1164/rccm.201408-1426OC.

Abstract

Rationale: 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.

Objectives: 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.

Measurements and main 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.

Keywords: bronchodilator; genotype; single-nucleotide polymorphism.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 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
  • Phenotype
  • Polymorphism, Single Nucleotide / genetics*
  • Receptors, Adrenergic, beta-2 / genetics
  • Respiratory Mechanics / genetics*
  • Suppressor of Cytokine Signaling Proteins / genetics*

Substances

  • ADRB2 protein, human
  • ASB3 protein, human
  • Adrenergic beta-2 Receptor Agonists
  • Bronchodilator Agents
  • Receptors, Adrenergic, beta-2
  • Suppressor of Cytokine Signaling Proteins

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