Genome-Wide Association Study of Short-Acting beta(2)-Agonists A Novel Genome-Wide Significant Locus on Chromosome 2 near ASB3

Elliot Israel, Jessica Lasky-Su, Amy Markezich, Amy Damask, Stanley J. Szefler, Brooke Schuemann, Barbara Klanderman, Jody Sylvia, Shamsah Kazani, Rongling Wu, Fernando Martinez, Homer A. Boushey, Vernon M. Chinchilli, Dave Mauger, Scott T. Weiss, Kelan G. Tantisira*, SHARP Investigators

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

24 Citations (Scopus)

Abstract

Rationale: [beta(2)-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 beta(2)-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 after correcting for multiple comparisons. Combined P values for rs350729, rs1840321, rs1384918, and rs1319797 were 2:21 X 10(-10), 5.75 X 10(-8), 9.3 X 10(-8), 3.95 X 10(-8), respectively. The significant variants all map to a novel genetic region on chromosome 2 neat 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.

Original languageEnglish
Pages (from-to)530-537
Number of pages8
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume191
Issue number5
DOIs
Publication statusPublished - 1-Mar-2015

Keywords

  • single-nucleotide polymorphism
  • genotype
  • bronchodilator
  • OBSTRUCTIVE PULMONARY-DISEASE
  • ASTHMA MANAGEMENT PROGRAM
  • BRONCHODILATOR RESPONSE
  • BETA(2)-ADRENERGIC RECEPTOR
  • CHILDHOOD ASTHMA
  • SKELETAL-MUSCLE
  • ANKYRIN REPEAT
  • BINDING-PROTEINS
  • RARE VARIANTS
  • BETA-AGONIST

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