The C523Aβ2Adrenergic Receptor Polymorphism Associates with Markers of Asthma Severity in African Americans

Lima, John J.; Holbrook, Janet T.; Wang, Jianwei; Sylvester, James E.; Blake, Kathryn; Blumenthal, Malcolm N.; Castro, Mario; Hanania, N.A.; Wise, Robert A.

doi:10.1080/02770900600566611

Cited by 19 publications

(26 citation statements)

References 46 publications

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“…More than a dozen additional SNPs have been reported, but many of them are rare, and the available knowledge on their functional relevance is limited for all of them, particularly with regard to drug-response studies (Brodde, 2008). The genotypes Gly16 and Glu27 are frequent in whites (approximately 50%), but a somewhat different prevalence may exist in other ethnicities (Table 1) (Hawkins et al, 2006;Lima et al, 2006;Wu et al, 2006). Genotype-phenotype association studies for the frequent R16G and Q27E variants have largely remained inconclusive with regard to arterial hypertension and other cardiovascular diseases (Hahntow et al, 2006;Rosskopf et al, 2007).…”

Section: Pharmacogenomics Of Gpcr Ligands In Cardiovascular Medicinementioning

confidence: 99%

Pharmacogenomics of G Protein-Coupled Receptor Ligands in Cardiovascular Medicine

Rosskopf

Michel²

2008

Pharmacol Rev

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Section: Pharmacogenomics Of Gpcr Ligands In Cardiovascular Medicinementioning

confidence: 99%

Pharmacogenomics of G Protein-Coupled Receptor Ligands in Cardiovascular Medicine

Rosskopf

Michel²

2008

Pharmacol Rev

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“…Haplotype associations were noted for the bronchoprotection, but not for the acute bronchodilator effect. Several other studies have shown associations with ␤ 2 AR 5Ј-flanking SNPs or haplotypes and agonist (or related) phenotypes (18)(19)(20). Of note, in these latter studies in particular, haplotypes were often "reduced" to encompass one or two individual SNPs in the coding region based on linkage disequilibrium and the limited number of patients with certain haplotypes.…”

Section: Table 2 Results Of Electrophoretic Mobility Shift Assay Stumentioning

confidence: 99%

“…The intronless ␤ 2 AR gene has at least 20 polymorphisms in the promoter, 5ЈUTR, and 5Ј-leader cistron (collectively termed here as the "5Ј-flanking region"), which have allele frequencies of 0.05 (5%) in U.S. individuals of European or African descent (11,14). Clinical studies (11,(15)(16)(17)(18)(19)(20) using haplotypes derived from various sets of 5Ј-flanking and coding single-nucleotide polymorphisms (SNPs) have revealed several, and sometimes discordant, findings (see Discussion). To begin to understand the basis for in vitro and clinical phenotypes, in the current study, we have examined each polymorphism within the context of the binding of transcription factors derived from both human airway smooth muscle and airway epithelial cells.…”

mentioning

confidence: 99%

Allele-Specific Binding of Airway Nuclear Extracts to Polymorphic β₂-Adrenergic Receptor 5′ Sequence

Panebra

Schwarb²,

Glinka³

et al. 2007

Am J Respir Cell Mol Biol

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Like other intronless G protein-coupled receptor genes, the ␤ 2 -adrenergic receptor (␤ 2 AR) has minimal genetic space for population variability, and has attained such via multiple coding and noncoding polymorphisms. Yet most clinical studies use the two nonsynonymous polymorphisms of the coding region for association analysis despite low levels of linkage disequilibrium with some promoter and 5UTR polymorphisms. To assess the potential for allele-specific transcription factor binding to ␤ 2 AR 5-flanking sequence, 3-biotin-labeled oligonucleotide duplexes were synthesized. Each was centered on variable sites representing major or minor alleles found in the human population with frequencies of 5% or greater (20 polymorphic sites). Electrophoretic mobility shift assays were performed using human airway smooth muscle or airway epithelial cell nuclear extracts. Many of these polymorphisms resulted in an alteration in binding, and both major allele and minor allele dominance were observed. For example, in airway smooth muscle nuclear extracts, 10 polymorphisms decreased and 2 increased binding, whereas 5 showed no differences. Concordance between airway smooth muscle and epithelial cell nuclear extract binding to polymorphic alleles was found in only ‫ف‬ 50% of cases. There was no tendency for the rare variants to be more likely to have altered nuclear extract binding compared to the more common variants. Taken together, these results provide potential mechanisms by which ␤ 2 AR 5-flanking polymorphisms affect obstructive lung phenotypes.Keywords: asthma; ␤-agonist; polymorphismThe ␤ 2 -adrenergic receptor (␤ 2 AR) gene is highly polymorphic in the human population within both the coding and noncoding regions. Within the coding block, two nonsynonymous polymorphisms are common, occurring at nucleotides 46 and 79 relative to the ATG start site (1). These result in Arg or Gly at amino acid 16 and Glu or Gln at position 27, with three of the four possible two-site haplotypes being prevalent in normal cohorts as well as those with asthma and chronic obstructive lung disease. An infrequent, nonsynonymous polymorphism at nucleotide 491 results in a substitution of Ile for Thr at amino acid 164 (1). These polymorphisms have been studied in recombinant systems whereby constructs (without cognate 5ЈUTR or promoter) were used to stably or transiently transfect model cells, such as fibroblasts (2, 3) and COS cells (4). These studies revealed several phenotypes of the polymorphic receptors, including those related to agonist-promoted receptor trafficking and receptor coupling to G s (see Refs. 5 and 6 for review). Given the interindividual variability in the response to ␤-agonists in asthma, of which ‫ف‬ 50% has been attributed to genetic variation (7), these polymor- CLINICAL RELEVANCEThe variability in the response to ␤-agonists in obstructive lung disease is not fully understood. We show that polymorphisms in the promoter 5Ј-flanking region of the receptor alter transcription factor binding. phisms of the ␤ 2 AR have been...

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“…Due to these results, it has been hypothesized that genetic polymorphisms in the β 2 -adrenergic receptor may have influenced the response to salmeterol because the frequency of polymorphisms in the β 2 -adrenergic receptor occur more frequently in African-Americans compared with the overall population 11,27,28 . However, the impact of these genetic polymorphisms on serious asthma outcomes is unclear, and existing data indicate that genotype may not affect the phenotypic response to salmeterol 22 .…”

Section: The Smart Studymentioning

confidence: 97%

Part IV: Genetic variations in β₂-adrenergic receptors: long-acting and short-acting β₂-agonists and therapeutic response

Peters

2007

Current Medical Research and Opinion

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Inhaled beta2-agonists are the most commonly used treatment for asthma. It has been hypothesized that patients who exhibit functional polymorphic variants of the beta2-adrenergic receptor may be more likely to experience adverse outcomes with the regular use of beta2-agonists, particularly the short-acting beta2-agonist albuterol. This hypothesis has been confirmed in retrospective studies and in a prospective clinical trial. Results from these studies demonstrate that patients with the Arg/Arg phenotype at the 16th amino acid position of the beta2-adrenergic receptor may experience worsening asthma outcomes after regular beta2-agonist use. Data regarding the impact of polymorphic variants of the beta2-adrenergic receptor on response to long-acting beta2-agonists are conflicting. However, recent data indicate that use of long-acting beta2-agonists may be associated with an increased risk of life-threatening asthma or asthma-related deaths, which might be increased among African-Americans and patients who do not use inhaled corticosteroids. Until more data are available, short-acting beta-agonists should only be used on an as-needed basis and to prevent exercise-induced asthma symptoms, and long-acting beta-agonists should only be used as an adjunct to controller therapy with inhaled corticosteroids. Any patient with asthma who requires adjunctive use of a long-acting beta2-agonist in addition to an inhaled corticosteroid should be carefully monitored for possible adverse asthma outcomes.

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The C523Aβ₂Adrenergic Receptor Polymorphism Associates with Markers of Asthma Severity in African Americans

Cited by 19 publications

References 46 publications

Pharmacogenomics of G Protein-Coupled Receptor Ligands in Cardiovascular Medicine

Pharmacogenomics of G Protein-Coupled Receptor Ligands in Cardiovascular Medicine

Allele-Specific Binding of Airway Nuclear Extracts to Polymorphic β₂-Adrenergic Receptor 5′ Sequence

Part IV: Genetic variations in β₂-adrenergic receptors: long-acting and short-acting β₂-agonists and therapeutic response

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The C523Aβ2Adrenergic Receptor Polymorphism Associates with Markers of Asthma Severity in African Americans

Cited by 19 publications

References 46 publications

Pharmacogenomics of G Protein-Coupled Receptor Ligands in Cardiovascular Medicine

Pharmacogenomics of G Protein-Coupled Receptor Ligands in Cardiovascular Medicine

Allele-Specific Binding of Airway Nuclear Extracts to Polymorphic β2-Adrenergic Receptor 5′ Sequence

Part IV: Genetic variations in β2-adrenergic receptors: long-acting and short-acting β2-agonists and therapeutic response

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Product

Resources

About

The C523Aβ₂Adrenergic Receptor Polymorphism Associates with Markers of Asthma Severity in African Americans

Allele-Specific Binding of Airway Nuclear Extracts to Polymorphic β₂-Adrenergic Receptor 5′ Sequence

Part IV: Genetic variations in β₂-adrenergic receptors: long-acting and short-acting β₂-agonists and therapeutic response