Family-based association analysis of β2-adrenergic receptor polymorphisms in the childhood asthma management program

doi:10.1016/S0091-6749(03)02023-2

Journal of Allergy and Clinical Immunology

Volume 112, Issue 5, November 2003, Pages 870-876

https://doi.org/10.1016/S0091-6749(03)02023-2 Get rights and content

Abstract

Background

β₂-Adrenergic receptor (B2AR) polymorphisms have been associated with a variety of asthma-related phenotypes, but association results have been inconsistent across different studies.

Objective

We sought to apply family-based association methods to individual single nucleotide polymorphisms (SNPs) and haplotypes of SNPs in B2AR to define the relationship of these genetic variants to asthma-related phenotypes.

Methods

DNA samples were obtained from 707 Childhood Asthma Management Program participants, representing 650 sibships, as well as their parents. Genotyping was performed at 8 B2AR SNPs. Qualitative asthma-related phenotypes were analyzed with single SNPs and haplotypes by using TRANSMIT; quantitative asthma-related phenotypes were analyzed with the Family-Based Association Test.

Results

Several SNPs, including SNP −654 and SNP +46, demonstrated significant associations (P < .05) to postbronchodilator FEV₁ as both a qualitative (<80% of predicted value) and quantitative phenotype. Quantitative phenotypic association analysis demonstrated significant evidence for association of SNP +523 with bronchodilator responsiveness expressed as a percentage of baseline FEV₁ (P = .012) or a percentage of predicted FEV₁ (P = .008). Similar evidence for association between the +523 SNP and qualitative bronchodilator responsiveness phenotypes was also found. Analysis of haplotypes supported an association of B2AR variants with spirometric values and bronchodilator responsiveness.

Conclusion

B2AR variants are associated with spirometric values and bronchodilator responsiveness, but different regions of the gene provide evidence for association with these phenotypes.

Section snippets

Study participants

The CAMP was a multicenter randomized clinical trial comparing an inhaled steroid medication (budesonide), nedocromil, and placebo in children with mild-to-moderate asthma. Baseline spirometric data were collected on 1041 CAMP participants at least 4 weeks after their last oral steroid course. Subsequently, a 28-day run-in period was performed, during which only as-needed inhaled bronchodilator medication was used, and daily diary records of peak expiratory flow rates (PEFRs) and asthma symptom

Demographics and phenotype values in CAMP participants

Mean phenotype values for the 707 CAMP participants included in this analysis are available in the Journal's Online Repository (at www.mosby.com/jaci) in Table E1. Seven participants from the CAMP pilot study who met the same criteria for asthma diagnosis as the randomized CAMP participants were included in the analysis; asthma affection status was the only phenotype available for those subjects. Among the 700 nonpilot study CAMP participants, the distribution of reported ethnicity was as

Discussion

To assess the role of B2AR variants in determining different asthma-related phenotypes, we performed a large family-based study of exceptionally well-phenotyped asthmatic patients from the Childhood Asthma Management Program. Eight individual SNPs and haplotypes of these 8 SNPs were included; we found the same 3 common B2AR haplotypes in CAMP that were observed by Drysdale et al.⁶

We found associations between spirometric measures, including postbronchodilator FEV₁ and FVC values, with variants

Acknowledgements

We appreciate assistance from the CAMP Research Group in recruiting subjects and collecting data for the CAMP Genetics Ancillary Study. We would like to acknowledge helpful discussions with Drs Steven Shapiro and Alan Templeton.

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Association of Beta 2 adrenergic receptor (Thr164Ile) polymorphism with Salbutamol refractoriness in severe asthmatics from Indian population
2016, Gene
Thr164Ile polymorphism in the ADRB2 gene encoding β2 adrenergic receptor (β₂AR) has its functional consequence in declining ligand-receptor interactions and depressed coupling of β₂AR to adenylcyclase. In the present study, we sought to evaluate the possible association of Thr164Ile polymorphism with asthma susceptibility, pharmacogenetic response to Salbutamol and varying degrees of severity.
Three hundred and ninety eight clinically diagnosed patients and four hundred and fifty six healthy controls were enrolled in the study. Patients were classified into severity classes according to the Global Initiative for Asthma (GINA) guidelines. To assess bronchodilator response, spirometry was performed before and 15 min after Salbutamol (200 μg) delivery. Responders to Salbutamol were categorized if percentage reversibility was greater than or equal to 12% in them, while those showing reversibility < 12% were classified as non-responders. Further, responding phenotypes were stratified into severity groups. Genotyping was carried out by ARMS-PCR technique. Statistical methods were applied to test the significance of the results.
In the present study, polymorphism was not associated with disease susceptibility however; there was significant association with non-responding asthmatics. In case of severity subsets, the polymorphism was not associated with milder subtypes; although, notable association was observed with moderate and severe asthma subtypes. In addition, the polymorphism was significantly associated with non-responding patients with severe asthma.
In south Indian population, the ADRB2 Thr164Ile polymorphism may not form susceptible variant to develop asthma, however, it can form a predictive maker for bronchodilator (Salbutamol) response in severe asthmatics.
Childhood asthma exacerbations and the Arg16 β<inf>2</inf>-receptor polymorphism: A meta-analysis stratified by treatment
2016, Journal of Allergy and Clinical Immunology
Citation Excerpt :
The pharmacogenetics of LABAs and SABAs are notable for the contrasting effects seen for the Gly16Arg locus on acute versus chronic SABAs. There has been considerable consistency in the observed effects of Gly16Arg on acute SABA response, with many studies showing a similar direction of effect on bronchodilation (favoring Arg16).6,7,11,25,26 A seemingly opposite effect (favoring Gly16) was seen for chronic SABA exposure and lung function and asthma control in the Beta Agonists in Mild Asthma27 and Beta-Adrenergic Response by Genotype28 studies and another study by Taylor et al.29 The focus of the present study was LABA therapy, but we found no evidence for either daily SABA use or the combination of a daily SABA plus LABA being linked to increased exacerbation risk for children carrying the Arg16 allele.
The Gly-to-Arg substitution at the 16 position (rs1042713) in the β₂-adrenoceptor gene (ADRB2) is associated with enhanced downregulation and uncoupling of β₂-receptors.
We sought to undertake a meta-analysis to test the hypothesis that there is an interaction between the A allele of rs1042713 (Arg16 amino acid) and long-acting β-agonist (LABA) exposure for asthma exacerbations in children.
Children with diagnosed asthma were recruited in 5 populations (BREATHE, Genes-Environments and Admixture in Latino Americans II, PACMAN, the Paediatric Asthma Gene Environment Study, and the Pharmacogenetics of Adrenal Suppression with Inhaled Steroid Study). A history of recent exacerbation and asthma treatment was determined from questionnaire data. DNA was extracted, and the Gly16Arg genotype was determined.
Data from 4226 children of white Northern European and Latino origin were analyzed, and the odds ratio for exacerbation increased by 1.52 (95% CI, 1.17-1.99; P = .0021) for each copy of the A allele among the 637 children treated with inhaled corticosteroids (ICSs) plus LABAs but not for treatment with ICSs alone (n = 1758) or ICSs plus leukotriene receptor antagonist (LTRAs; n = 354) or ICSs plus LABAs plus LTRAs (n = 569).
The use of a LABA but not an LTRA as an “add-on controller” is associated with increased risk of asthma exacerbation in children carrying 1 or 2 A alleles at rs1042713. Prospective genotype-stratified clinical trials are now required to explore the potential role of rs1042713 genotyping for personalized asthma therapy in children.
Genetics in Asthma and COPD
2015, Murray and Nadel's Textbook of Respiratory Medicine: Volume 1,2, Sixth Edition
Genetics of Allergic Diseases
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The β2-adrenoreceptor gene promoter polymorphisms may modulate β2-agonist- and glucocorticoid-induced IgE synthesis
2014, Allergologia et Immunopathologia
β2-adrenoreceptor (β2-AR) agonists and glucocorticoids (GCS) were shown to induce IgE synthesis in human PBMCs. Serum total IgE levels are associated with single nucleotide polymorphisms (SNPs) of the β2-AR gene. We aimed to assess the association of the effect of fenoterol (β2-AR agonist) on IL-4-driven and budesonide-induced IgE synthesis with genetic variants of β2-AR.
The study included 25 individuals: 13 with allergic asthma and/or allergic rhinitis and 12 healthy volunteers. PBMCs were cultured with IL-4, fenoterol and/or budesonide, and IgE concentrations in supernatants were assessed. Five SNPs in positions: −47, −20, 46, 79 and 252 of β2-AR were determined by direct DNA sequencing.
In −47 T/T and −20 T/T patients, incubation with fenoterol resulted in decreased IgE production, whereas in −47 C/T and −47 C/C as well as in −20 C/T and −20 C/C individuals, it was enhanced. In contrast to fenoterol, budesonide-induced IgE synthesis was significantly increased in −47 T/T and −20 T/T patients as compared to −47 C/T, −47 C/C, −20 C/T and −47 C/C individuals. Polymorphisms in positions 46, 79 and 252 were not associated with fenoterol- or budesonide-modulated IgE synthesis. No differences in the distribution of IgE synthesis was seen between atopic and non-atopic individuals carrying the same alleles.
The differential effect of β2-agonists and GCS on IgE synthesis may be associated with genetic variants of promoter region of the β2-AR gene.
Inhaled corticosteroid treatment modulates ZNF432 gene variant's effect on bronchodilator response in asthmatics
2014, Journal of Allergy and Clinical Immunology
Single nucleotide polymorphisms (SNPs) influence a patient’s response to inhaled corticosteroids and β₂-agonists, and the effect of treatment with inhaled corticosteroids is synergistic with the effect of β₂-agonists. We hypothesized that use of inhaled corticosteroids could influence the effect of SNPs associated with a bronchodilator response.
To assess whether, among subjects with asthma, the association of SNPs with bronchodilator response is different between those treated with inhaled corticosteroids versus those on placebo.
A genome-wide association analysis was conducted by using 581 white subjects from the Childhood Asthma Management Program. By using data for 449,540 SNPs, we conducted a gene by environment analysis in PLINK with inhaled corticosteroid treatment as the environmental exposure and bronchodilator response as the outcome measure. We attempted to replicate the top 12 SNPs in the Leukotriene Modifier or Corticosteroid or Corticosteroid-Salmeterol Trial.
The combined P value for the Childhood Asthma Management Program and Leukotriene Modifier or Corticosteroid or Corticosteroid-Salmeterol Trial populations was 4.8 × 10⁻⁸ for rs3752120, which is located in the zinc finger protein gene ZNF432 and has an unknown function.
Inhaled corticosteroids appear to modulate the association of bronchodilator response with variant(s) in the ZNF432 gene among adults and children with asthma.

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^☆

The Childhood Asthma Management Program Genetics Ancillary Study was supported by National Institutes of Health Program for Genomic Applications Grant U01 HL 66795 and R01 HL66386 to the Channing Laboratory, Brigham and Women's Hospital.

The Childhood Asthma Management Program was supported by contracts N01-HR-16044, 16045, 16046, 16047, 16048, 16049, 16050, 16051, and 16052 from the National Heart, Lung, and Blood Institute.

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Asthma, rhinitis, other respiratory diseasesFamily-based association analysis of β2-adrenergic receptor polymorphisms in the childhood asthma management program☆

Abstract

Background

Objective

Methods

Results

Conclusion

Section snippets

Study participants

Demographics and phenotype values in CAMP participants

Discussion

Acknowledgements

Genomics

Am J Hum Genet

Am J Hum Genet

Am J Hum Genet

J Allergy Clin Immunol

Am J Hum Genet

Genetic susceptibility to asthma bronchial hyperresponsiveness coinherited with a major gene for atopy

N Engl J Med

A genome-wide search for asthma susceptibility loci in ethnically diverse populations

Nat Genet

Subsensitization of beta-adrenoceptors in airways and lymphocytes of healthy and asthmatic subjects

Am Rev Respir Dis

Beta2-adrenergic receptor genetics

Curr Opin Mol Ther

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

Proc Natl Acad Sci U S A

The Childhood Asthma Management Program (CAMP): design, rationale, and methods

Control Clin Trials

Long-term effects of budesonide or nedocromil in children with asthma

N Engl J Med

Asthma, rhinitis, other respiratory diseases
Family-based association analysis of β₂-adrenergic receptor polymorphisms in the childhood asthma management program☆