title: beta(2)-adrenergic receptor promoter haplotype influences spirometric response during an acute asthma exacerbation.
abstract: Genetic variants in the beta(2)-adrenergic receptor (ADRB2) coding block have been associated with different parameters of asthma severity, but there is no consensus on which variants are most important. Our objective was to determine whether the genetic variants in the 5'- or 3'-flanking regions of ADRB2 impact the response to therapy. DNA was obtained initially from 72 adults hospitalized for an asthma exacerbation. We sequenced a 5,000 bp region of the ADRB2 gene that spanned the flanking regions and identified 31 single nucleotide polymorphisms (SNPs). Nonresponders to asthma therapy were defined as patients whose forced expiratory volume in 1 second (FEV(1)) worsened by >10% at 24 hours after admission. We then evaluated the relationship between the 19 common SNPs and response to asthma-specific therapy during acute disease exacerbations. Our results showed a significant association between nonresponders and a haplotype of five promoter SNPs in a nearly complete linkage disequilibrium. An analysis of the promoter and coding block polymorphisms in an extended cohort of 99 patients confirmed that promoter haplotype was the genetic component most strongly associated with asthmatic nonresponders, which was statistically significant among whites (p < 0.05). An identification of this promoter haplotype may provide an alternate explanation for the variation in the asthma responses observed with ADRB2 coding block polymorphisms.
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: Paul E
authors.initials: PE
authors.lastname: Moore
authors.forename: Scott M
authors.initials: SM
authors.lastname: Williams
authors.forename: Tebeb
authors.initials: T
authors.lastname: Gebretsadik
authors.forename: Lan
authors.initials: L
authors.lastname: Jiang
authors.forename: Patricia L
authors.initials: PL
authors.lastname: Minton
authors.forename: Ayumi
authors.initials: A
authors.lastname: Shintani
authors.forename: John A
authors.initials: JA
authors.lastname: Phillips Iii
authors.forename: Elliott P
authors.initials: EP
authors.lastname: Dawson
authors.forename: Tina V
authors.initials: TV
authors.lastname: Hartert
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D001249:Asthma / Q000209:etiology / Q000235:genetics* / Q000503:physiopathology*; D015331:Cohort Studies; D003710:Demography; D005541:Forced Expiratory Volume / Q000235:genetics; D005787:Gene Frequency; D006239:Haplotypes / Q000235:genetics*; D006760:Hospitalization; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics*; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics*; D013147:Spirometry
chemical_list: D018343:Receptors, Adrenergic, beta-2