Genome-Wide Association Study of Short-Acting β₂-Agonists. A Novel Genome-Wide Significant Locus on Chromosome 2 near ASB3

Abstract

Rationale: b 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 b 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 3 10 210 , 5.75 3 10 28 , 9.3 3 10 28 , and 3.95 3 10 28 , 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. Supported by National Institutes of Health (NIH) U01 HL65899, R01 NR013391, and R01 HL092197. SHARP was funded by NIH U10 HL74231, U01 HL65899, U54LM8748, U01 HL75232, U01 HL75408, U01 HL75409, U01 HL75415, U01 HL75416, U01 HL75417, U01 HL75419, U01 HL75420, U10 HL64287, U10 HL64288, U10 HL64295, U10 HL64305, U10 HL64307, U01 HL64313, U10 HL51831, U10 HL51834, U10 HL51843, U10 HL51810, U10 HL51823, U10 HL51845, and U10 HL56443. The full SHARP acknowledgment can be found in the online supplement. The NHLBI SHARe (SNP Health Association Resource) genotyping services were provided by Affymetrix, Inc. under U.S. Federal Government contract number N02-HL-6-4278 from the NHLBI, the NIH GWAS Repository of Genotype and Phenotype data (termed dbGaP) (http://www.ncbi.nlm.nih.gov/sites/entrez?db=gap) was developed by the NIH National Center for Biotechnology Information to archive and distribute the results of studies that have investigated the interaction of genotype and phenotype in genome-wide association studies. The dbGaP project accession number for SHARP (SHARe Asthma Resource Project) is phs000166.v2.p1.

Genetics of allergy and allergic sensitization: common variants, rare mutations

“…Ethnic differences have been demonstrated in allergy-related GWAS [23] and will be the focus of future studies including larger non-European populations. Also, future larger GWAS will have increased power to target gene by environment interactions and directly clinically relevant phenotypes, such as response to medication [24•]. …”

Treatment response heterogeneity in asthma: the role of genetic variation

“…The most significant results were subsequently replicated in an independent population of 439 adult asthmatics [16]. Three SNPs in one region in chromosome 2 were associated with BDR.…”

Molecular Genetics of Asthma

“…Other technology released was the Sequencing by Oligo Ligation Detection in 2007 [ 48 ]. The platform employs fragmented and amplifi ed DNA samples by emPCR on which sequencing is performed b y ligation method.…”

“…Supershift and competition assays revealed that C/EBPb and members of the Sp and GATA families are differentially bound at PTGDR promoter region containing the SNPs and that the different SNPs modify the binding [ 48 ]. In 2011, our group researched PTGDR in asthmatic patients.…”

“…Mouse strains can be classifi ed according to the capacity of developing airway infl ammation and AHR. There are responder strains, such as A/J and AKR/J with high levels of AHR to methacholine [ 47 ] or non-responder strains, as the C3H/HeJ or DBA/2, that are resistant to allergen-induced AHR [ 48 ]. However, the most used are the BALB/c and C57B/6 strains because their immune response is well characterized.…”