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.
|Number of pages||8|
|Journal||American Journal of Respiratory and Critical Care Medicine|
|Publication status||Published - 1-Mar-2015|
- single-nucleotide polymorphism
- OBSTRUCTIVE PULMONARY-DISEASE
- ASTHMA MANAGEMENT PROGRAM
- BRONCHODILATOR RESPONSE
- BETA(2)-ADRENERGIC RECEPTOR
- CHILDHOOD ASTHMA
- ANKYRIN REPEAT
- RARE VARIANTS