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            -Adrenergic Receptor Polymorphisms and Response to Salbutamol Among Indian Asthmatics
            <sup>*</sup>

Kukreti, Ritushree; Bhatnagar, Pallav; B-Rao, Chandrika; Gupta, Saloni; Madan, Babita; Das, Chinmoyee; Guleria, Randeep; Athavale, Amita; Brahmachari, Samir K.; Ghosh, Balaram

doi:10.1517/14622416.6.4.399

Cited by 35 publications

(32 citation statements)

References 32 publications

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“…Similar results have been reported in multiple other populations, suggesting they are correct [49,50,52]. However, replication attempted in the Indian population reported exactly the opposite effect of these genotypes [53], and others have found either no difference between Gly16 and Arg16 receptor variants [44] or decrease in response in mild asthmatics carrying the homozygous Arg16 genotype that [54].…”

Section: And Corticosteroidssupporting

confidence: 84%

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Recent development in pharmacogenomics: from candidate genes to genome-wide association studies

Grant¹,

Hákonarson²

2007

Expert Review of Molecular Diagnostics

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Genetic diversity, most notably through single nucleotide polymorphisms and copy-number variation, together with specific environmental exposures, contributes to both disease susceptibility and drug response variability. It has proved difficult to isolate disease genes that confer susceptibility to complex disorders, and as a consequence, even fewer genetic variants that influence clinical drug responsiveness have been uncovered. As such, the candidate gene approach has largely failed to deliver and, although the family-based linkage approach has certain theoretical advantages in dealing with common/complex disorders, progress has been slower than was hoped. More recently, genome-wide association studies have gained increasing popularity, as they enable scientists to robustly associate specific variants with the predisposition for complex disease, such as age-related macular degeneration, Type 2 diabetes, inflammatory bowel disease, obesity, autism and leukemia. This relatively new methodology has stirred new hope for the mapping of genes that regulate drug response related to these conditions. Collectively, these studies support the notion that modern high-throughput single nucleotide polymorphism genotyping technologies, when applied to large and comprehensively phenotyped patient cohorts, will readily reveal the most clinically relevant disease-modifying and drug response genes. This review addresses both recent advances in the genotyping field and highlights from genome-wide association studies, which have conclusively uncovered variants that underlie disease susceptibility and/or variability in drug response in common disorders.

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Section: And Corticosteroidssupporting

confidence: 84%

“…Others have not found such a striking difference in studies including both pediatric [53] and adult patients [37]. In a study addressing …”

Section: And Corticosteroidsmentioning

confidence: 95%

Recent development in pharmacogenomics: from candidate genes to genome-wide association studies

Grant¹,

Hákonarson²

2007

Expert Review of Molecular Diagnostics

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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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“…38 Additionally, in an Indian population, response to salbutamol treatment of asthmatic patients depends on polymorphisms of the beta 2 adrenergic receptor. 39 …”

Section: Antihypertensive Drugs and Receptorsmentioning

confidence: 99%

Pharmacogenetics and the concept of individualized medicine

2005

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β ₂ -Adrenergic Receptor Polymorphisms and Response to Salbutamol Among Indian Asthmatics ^*

Abstract: This study suggests that the SNP at nucleotide position 46 has particular relevance to pharmacogenetics in the Indian population studied.

Cited by 35 publications

References 32 publications

Recent development in pharmacogenomics: from candidate genes to genome-wide association studies

Recent development in pharmacogenomics: from candidate genes to genome-wide association studies

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

Pharmacogenetics and the concept of individualized medicine

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β 2 -Adrenergic Receptor Polymorphisms and Response to Salbutamol Among Indian Asthmatics *

Abstract: This study suggests that the SNP at nucleotide position 46 has particular relevance to pharmacogenetics in the Indian population studied.

Cited by 35 publications

References 32 publications

Recent development in pharmacogenomics: from candidate genes to genome-wide association studies

Recent development in pharmacogenomics: from candidate genes to genome-wide association studies

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

Pharmacogenetics and the concept of individualized medicine

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Product

Resources

About

β ₂ -Adrenergic Receptor Polymorphisms and Response to Salbutamol Among Indian Asthmatics ^*

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