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.
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.
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Authors: Angel C Y Mak; Marquitta J White; Walter L Eckalbar; Zachary A Szpiech; Sam S Oh; Maria Pino-Yanes; Donglei Hu; Pagé Goddard; Scott Huntsman; Joshua Galanter; Ann Chen Wu; Blanca E Himes; Soren Germer; Julia M Vogel; Karen L Bunting; Celeste Eng; Sandra Salazar; Kevin L Keys; Jennifer Liberto; Thomas J Nuckton; Thomas A Nguyen; Dara G Torgerson; Pui-Yan Kwok; Albert M Levin; Juan C Celedón; Erick Forno; Hakon Hakonarson; Patrick M Sleiman; Amber Dahlin; Kelan G Tantisira; Scott T Weiss; Denise Serebrisky; Emerita Brigino-Buenaventura; Harold J Farber; Kelley Meade; Michael A Lenoir; Pedro C Avila; Saunak Sen; Shannon M Thyne; William Rodriguez-Cintron; Cheryl A Winkler; Andrés Moreno-Estrada; Karla Sandoval; Jose R Rodriguez-Santana; Rajesh Kumar; L Keoki Williams; Nadav Ahituv; Elad Ziv; Max A Seibold; Robert B Darnell; Noah Zaitlen; Ryan D Hernandez; Esteban G Burchard Journal: Am J Respir Crit Care Med Date: 2018-06-15 Impact factor: 30.528