Childhood asthma exacerbations and the Arg16 β2-receptor polymorphism

a meta-analysis stratified by treatment

Steve Turner, Ben Francis, Susanne Vijverberg, Maria Pino-Yanes, Anke H Maitland-van der Zee, Kaninika Basu, Lauren Bignell, Somnath Mukhopadhyay, Roger Tavendale, Colin Palmer, Daniel Hawcutt , Munir Pirmohamed, Esteban G Burchard, Brian Lipworth

Research output: Contribution to journalArticle

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Abstract

Background

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.

Objectives

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.

Methods

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.

Results

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).

Conclusions

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.
Original languageEnglish
Pages (from-to)107-113
Number of pages7
JournalJournal of Allergy and Clinical Immunology
Volume138
Issue number1
Early online date7 Jan 2016
DOIs
Publication statusPublished - Jul 2016

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Meta-Analysis
Asthma
Adrenal Cortex Hormones
Alleles
Hispanic Americans
Therapeutics
Genotype
Genes
Leukotriene Antagonists
Adrenergic Receptors
Down-Regulation
Odds Ratio
Steroids
Clinical Trials
Pediatrics
Amino Acids
DNA
Population

Keywords

  • adrenergic receptors
  • asthma
  • child
  • disease exacerbation
  • therapeutics

Cite this

Childhood asthma exacerbations and the Arg16 β2-receptor polymorphism : a meta-analysis stratified by treatment . / Turner, Steve; Francis, Ben; Vijverberg, Susanne; Pino-Yanes, Maria; Maitland-van der Zee, Anke H; Basu, Kaninika; Bignell, Lauren; Mukhopadhyay, Somnath; Tavendale, Roger; Palmer, Colin; Hawcutt , Daniel ; Pirmohamed, Munir ; Burchard, Esteban G ; Lipworth, Brian.

In: Journal of Allergy and Clinical Immunology, Vol. 138, No. 1, 07.2016, p. 107-113.

Research output: Contribution to journalArticle

Turner, S, Francis, B, Vijverberg, S, Pino-Yanes, M, Maitland-van der Zee, AH, Basu, K, Bignell, L, Mukhopadhyay, S, Tavendale, R, Palmer, C, Hawcutt , D, Pirmohamed, M, Burchard, EG & Lipworth, B 2016, 'Childhood asthma exacerbations and the Arg16 β2-receptor polymorphism: a meta-analysis stratified by treatment ', Journal of Allergy and Clinical Immunology, vol. 138, no. 1, pp. 107-113. https://doi.org/10.1016/j.jaci.2015.10.045
Turner, Steve ; Francis, Ben ; Vijverberg, Susanne ; Pino-Yanes, Maria ; Maitland-van der Zee, Anke H ; Basu, Kaninika ; Bignell, Lauren ; Mukhopadhyay, Somnath ; Tavendale, Roger ; Palmer, Colin ; Hawcutt , Daniel ; Pirmohamed, Munir ; Burchard, Esteban G ; Lipworth, Brian. / Childhood asthma exacerbations and the Arg16 β2-receptor polymorphism : a meta-analysis stratified by treatment . In: Journal of Allergy and Clinical Immunology. 2016 ; Vol. 138, No. 1. pp. 107-113.
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abstract = "BackgroundThe 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.ObjectivesWe 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.MethodsChildren 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.ResultsData 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).ConclusionsThe 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.",
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T1 - Childhood asthma exacerbations and the Arg16 β2-receptor polymorphism

T2 - a meta-analysis stratified by treatment

AU - Turner, Steve

AU - Francis, Ben

AU - Vijverberg, Susanne

AU - Pino-Yanes, Maria

AU - Maitland-van der Zee, Anke H

AU - Basu, Kaninika

AU - Bignell, Lauren

AU - Mukhopadhyay, Somnath

AU - Tavendale, Roger

AU - Palmer, Colin

AU - Hawcutt , Daniel

AU - Pirmohamed, Munir

AU - Burchard, Esteban G

AU - Lipworth, Brian

PY - 2016/7

Y1 - 2016/7

N2 - BackgroundThe 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.ObjectivesWe 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.MethodsChildren 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.ResultsData 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).ConclusionsThe 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.

AB - BackgroundThe 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.ObjectivesWe 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.MethodsChildren 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.ResultsData 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).ConclusionsThe 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.

KW - adrenergic receptors

KW - asthma

KW - child

KW - disease exacerbation

KW - therapeutics

U2 - 10.1016/j.jaci.2015.10.045

DO - 10.1016/j.jaci.2015.10.045

M3 - Article

VL - 138

SP - 107

EP - 113

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

SN - 0091-6749

IS - 1

ER -