Effect of β2 -adrenergic receptor gene Arg16Gly polymorphisms on response to long-acting β2-agonist in Chinese Han asthmatic patients

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Abstract

Background

To evaluate the effect of variation of the Arg16Gly polymorphism of the β ₂-adrenergic receptor gene on clinical response to salmeterol administered with fluticasone propionate in Chinese Han asthmatic patients.

Methods

Moderate persistent asthmatic patients (n = 62) currently receiving short-acting β ₂-agonists were administered twice-daily therapy with salmeterol/fluticasone propionate 50/250 μg in a single inhaler for 12 weeks, followed by a 2-to-4-day run-out period. Using direct DNA sequencing, five single nucleotide polymorphisms (SNPs) in the promoter and coding block regions of β ₂-adrenergic receptor gene were determined in 62 subjects and haplotypes were combined.

Results

There was sustained and significant improvement (p < 0.001) over baseline in all measures of asthma control in subjects receiving salmeterol and fluticasone, regardless of Arg16Gly genotype. However, there was no significant difference in the improvement among three genotypes (p > 0.05). Responses to salmeterol did not appear to be modified by haplotype pairs (p > 0.05). During the run-out period, all subjects had similar decreases in measures of asthma control, with no differences between genotypes (p > 0.05).

Conclusions

Response to salmeterol does not vary with Arg16Gly polymorphisms after chronic dosing with inhaled corticosteroids in Chinese Han asthmatic patients.

Related collections

Most cited references 17

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Complex promoter and coding region beta 2-adrenergic receptor haplotypes alter receptor expression and predict in vivo responsiveness.

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The human beta(2)-adrenergic receptor gene has multiple single-nucleotide polymorphisms (SNPs), but the relevance of chromosomally phased SNPs (haplotypes) is not known. The phylogeny and the in vitro and in vivo consequences of variations in the 5' upstream and ORF were delineated in a multiethnic reference population and an asthmatic cohort. Thirteen SNPs were found organized into 12 haplotypes out of the theoretically possible 8,192 combinations. Deep divergence in the distribution of some haplotypes was noted in Caucasian, African-American, Asian, and Hispanic-Latino ethnic groups with >20-fold differences among the frequencies of the four major haplotypes. The relevance of the five most common beta(2)-adrenergic receptor haplotype pairs was determined in vivo by assessing the bronchodilator response to beta agonist in asthmatics. Mean responses by haplotype pair varied by >2-fold, and response was significantly related to the haplotype pair (P = 0.007) but not to individual SNPs. Expression vectors representing two of the haplotypes differing at eight of the SNP loci and associated with divergent in vivo responsiveness to agonist were used to transfect HEK293 cells. beta(2)-adrenergic receptor mRNA levels and receptor density in cells transfected with the haplotype associated with the greater physiologic response were approximately 50% greater than those transfected with the lower response haplotype. The results indicate that the unique interactions of multiple SNPs within a haplotype ultimately can affect biologic and therapeutic phenotype and that individual SNPs may have poor predictive power as pharmacogenetic loci.

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Inference of haplotypes from PCR-amplified samples of diploid populations.

A Clark (1990)

Direct sequencing of genomic DNA from diploid individuals leads to ambiguities on sequencing gels whenever there is more than one mismatching site in the sequences of the two orthologous copies of a gene. While these ambiguities cannot be resolved from a single sample without resorting to other experimental methods (such as cloning in the traditional way), population samples may be useful for inferring haplotypes. For each individual in the sample that is homozygous for the amplified sequence, there are no ambiguities in the identification of the allele's sequence. The sequences of other alleles can be inferred by taking the remaining sequence after "subtracting off" the sequencing ladder of each known site. Details of the algorithm for extracting allelic sequences from such data are presented here, along with some population-genetic considerations that influence the likelihood for success of the method. The algorithm also applies to the problem of inferring haplotype frequencies of closely linked restriction-site polymorphisms.

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Use of regularly scheduled albuterol treatment in asthma: genotype-stratified, randomised, placebo-controlled cross-over trial.

Elliot Israel, Vernon M Chinchilli, Jean Ford … (2004)

The issue of whether regular use of an inhaled beta2-adrenergic agonist worsens airflow and clinical outcomes in asthma is controversial. Retrospective studies have suggested that adverse effects occur in patients with a genetic polymorphism that results in homozygosity for arginine (Arg/Arg), rather than glycine (Gly/Gly), at aminoacid residue 16 of the beta2-adrenergic receptor. However, the existence of any genotype-dependent difference has not been tested in a prospective clinical trial. Patients with mild asthma, not using a controller medication, were enrolled in pairs matched for forced expiratory volume in 1 s (FEV1) according to whether they had the Arg/Arg (n=37; four of 41 matches withdrew before randomisation) or Gly/Gly (n=41) genotype. Regularly scheduled treatment with albuterol or placebo was given in a masked, cross-over design, for 16-week periods. During the study, as-needed albuterol use was discontinued and ipratropium bromide was used as needed. Morning peak expiratory flow rate (PEFR) was the primary outcome variable. The primary comparisons were between treatment period for each genotype; the secondary outcome was a treatment by genotype effect. Analyses were by intention to treat. During the run-in period, when albuterol use was kept to a minimum, patients with the Arg/Arg genotype had an increase in morning PEFR of 23 L/min (p=0.0162); the change in patients with the Gly/Gly genotype was not significant (2 L/min; p=0.8399). During randomised treatment, patients with the Gly/Gly genotype had an increase in morning PEFR during treatment with regularly scheduled albuterol compared with placebo (14 L/min [95% CI 3 to 25]; p=0.0175). By contrast, patients with the Arg/Arg genotype had lower morning PEFR during treatment with albuterol than during the placebo period, when albuterol use was limited (-10 L/min [-19 to -2]; p=0.0209). The genotype-attributable treatment difference was therefore -24 L/min (-37 to -12; p=0.0003). There were similar genotype-specific effects in FEV1, symptoms, and use of supplementary reliever medication. Genotype at the 16th aminoacid residue of the beta2-adrenergic receptor affects the long-term response to albuterol use. Bronchodilator treatments avoiding albuterol may be appropriate for patients with the Arg/Arg genotype.

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Author and article information

Contributors

Yuying Qiu

Deping Zhang

Yu Qin

Kai-Sheng Yin

Journal

Journal ID (nlm-ta): Multidiscip Respir Med

Journal ID (iso-abbrev): Multidiscip Respir Med

Title: Multidisciplinary Respiratory Medicine

Publisher: BioMed Central

ISSN (Print): 1828-695X

ISSN (Electronic): 2049-6958

Publication date Collection: 2014

Publication date (Electronic): 11 April 2014

Volume: 9

Issue: 1

Page: 22

Affiliations

[1 ]Department of Respiratory Medicine, Drum Tower (Gulou) Hospital Affiliated to Nanjing University Medical School, 321 Zhongshan Road, Nanjing 210008, China

[2 ]Department of Non-Communicable Chronic Disease Control, Jiangsu Provincial Center for Disease Control and Prevention, 172 Jiangsu Road, Nanjing 210009, China

[3 ]Department of Respiratory Medicine, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, China

Article

Publisher ID: 2049-6958-9-22

DOI: 10.1186/2049-6958-9-22

PMC ID: 4013543

PubMed ID: 24721141

SO-VID: fd080ac9-5a32-424f-8626-55c1a3b645c7

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 23 December 2013

Date accepted : 28 March 2014

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