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; Pharmacogenomics in Childhood Asthma Consortium

doi:10.1016/j.jaci.2015.10.045

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, Pharmacogenomics in Childhood Asthma Consortium

Pharmacoepidemiology and Clinical Pharmacology

Research output: Contribution to journal › Article › Academic › peer-review

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 language	English
Journal	Journal of Allergy and Clinical Immunology
DOIs	https://doi.org/10.1016/j.jaci.2015.10.045
Publication status	Published - 7 Jan 2016

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10.1016/j.jaci.2015.10.045

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Turner, S., Francis, B., Vijverberg, S., Pino-Yanes, M., Maitland-van der Zee, A. H., Basu, K., Bignell, L., Mukhopadhyay, S., Tavendale, R., Palmer, C., Hawcutt, D., Pirmohamed, M., Burchard, E. G., Lipworth, B., & Pharmacogenomics in Childhood Asthma Consortium (2016). Childhood asthma exacerbations and the Arg16 β2-receptor polymorphism: A meta-analysis stratified by treatment. Journal of Allergy and Clinical Immunology. https://doi.org/10.1016/j.jaci.2015.10.045

@article{3fe82e5537594f35a61a58c871e95131,

title = "Childhood asthma exacerbations and the Arg16 β2-receptor polymorphism: A meta-analysis stratified by treatment",

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.",

author = "Steve Turner and Ben Francis and Susanne Vijverberg and Maria Pino-Yanes and {Maitland-van der Zee}, {Anke H} and Kaninika Basu and Lauren Bignell and Somnath Mukhopadhyay and Roger Tavendale and Colin Palmer and Daniel Hawcutt and Munir Pirmohamed and Burchard, {Esteban G} and Brian Lipworth and {Pharmacogenomics in Childhood Asthma Consortium}",

year = "2016",

month = jan,

day = "7",

doi = "10.1016/j.jaci.2015.10.045",

language = "English",

journal = "Journal of Allergy and Clinical Immunology",

issn = "0091-6749",

publisher = "Elsevier Inc.",

}

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 & Pharmacogenomics in Childhood Asthma Consortium 2016, 'Childhood asthma exacerbations and the Arg16 β2-receptor polymorphism: A meta-analysis stratified by treatment', Journal of Allergy and Clinical Immunology. https://doi.org/10.1016/j.jaci.2015.10.045

TY - JOUR

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

AU - Pharmacogenomics in Childhood Asthma Consortium

PY - 2016/1/7

Y1 - 2016/1/7

N2 - 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.

AB - 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.

U2 - 10.1016/j.jaci.2015.10.045

DO - 10.1016/j.jaci.2015.10.045

M3 - Article

C2 - 26774659

SN - 0091-6749

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

ER -

Childhood asthma exacerbations and the Arg16 β2-receptor polymorphism: A meta-analysis stratified by treatment

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