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

SHARP Investigators

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

Rationale: β2-Agonists are the most common form of treatment of asthma, but there is significant variability inresponse to thesemedications. 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 after correcting 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.

Original languageEnglish (US)
Pages (from-to)530-537
Number of pages8
JournalAmerican journal of respiratory and critical care medicine
Volume191
Issue number5
DOIs
StatePublished - Mar 1 2015

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Keywords

  • Bronchodilator
  • Genotype
  • Single-nucleotide polymorphism

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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