ADRB2 Haplotypes and Asthma Exacerbations in Children and Young Adults: An Individual Participant Data Meta-Analysis

Leila Karimi, Susanne J. Vijverberg, Marjolein Engelkes, Natalia Hernandez-Pacheco, Niloufar Farzan, Patricia Soares, Maria Pino-Yanes, Andrea L. Jorgensen, Celeste Eng, Somnath Mukhopadhyay, Maximilian Schieck, Michael Kabesch, Esteban G. Burchard, Fook Tim Chew, Yang Yie Sio, Uroš Potočnik, Mario Gorenjak, Daniel B. Hawcutt, Colin N. Palmer, Steve TurnerHettie M. Janssens, Anke H. Maitland-van der Zee, Katia M. C. Verhamme (Lead / Corresponding author),

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Background: The polymorphism Arg16 in β2 -adrenergic receptor (ADRB2) gene has been associated with an increased risk of exacerbations in asthmatic children treated with long-acting β2 -agonists (LABA). However, it remains unclear whether this increased risk is mainly attributed to this single variant or the combined effect of the haplotypes of polymorphisms at codons 16 and 27.

Objective: We assessed whether the haplotype analysis could explain the association between the polymorphisms at codons 16 (Arg16Gly) and 27 (Gln27Glu) in ADRB2 and risk of asthma exacerbations in patients treated with inhaled corticosteroids (ICS) plus LABA.

Methods: The study was undertaken using data from ten independent studies (n = 5,903) of the multi-ethnic Pharmacogenomics in Childhood Asthma (PiCA) consortium. Asthma exacerbations were defined as asthma-related use of oral corticosteroids or hospitalizations/emergency department visits in the past 6 or 12 months prior to the study visit/enrolment. The association between the haplotypes and the risk of asthma exacerbations was performed per study using haplo.stats package adjusted for age and sex. Results were meta-analyzed using the inverse variance weighting method assuming random-effects.

Results: In subjects treated with ICS and LABA (n = 832, age: 3-21 years), Arg16/Gln27 vs. Gly16/Glu27 (OR: 1.40, 95% CI: 1.05-1.87, I2 = 0.0%) and Arg16/Gln27 vs. Gly16/Gln27 (OR: 1.43, 95% CI: 1.05-1.94, I2 = 0.0%), but not Gly16/Gln27 vs. Gly16/Glu27 (OR: 0.99, 95% CI: 0.71-1.39, I2 = 0.0%), were significantly associated with an increased risk of asthma exacerbations. The sensitivity analyses indicated no significant association between the ADRB2 haplotypes and asthma exacerbations in the other treatment categories i.e., as-required short-acting β2 -agonists (n = 973), ICS monotherapy (n = 2,623), ICS plus leukotriene receptor antagonists (LTRA; n = 338), or ICS plus LABA plus LTRA (n = 686).

Conclusion and Clinical Relevance: The ADRB2 Arg16 haplotype, presumably mainly driven by the Arg16, increased the risk of asthma exacerbations in patients treated with ICS plus LABA. This finding could be beneficial in ADRB2 genotype-guided treatment which might improve clinical outcomes in asthmatic patients.

Original languageEnglish
Pages (from-to)1157-1171
Number of pages15
JournalClinical and Experimental Allergy
Issue number9
Early online date15 Jun 2021
Publication statusPublished - Sept 2021


  • ADRB2
  • asthma exacerbations
  • haplotypes
  • inhaled corticosteroids
  • long-acting β -agonists

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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