Arginine-16 β2 adrenoceptor genotype predisposes to exacerbations in young asthmatics taking regular salmeterol
- 1Population Pharmacogenetics Group, Biomedical Research Centre, University of Dundee, UK
- 2Division of Medicine and Therapeutics, Asthma and Allergy Unit, Ninewells Hospital and Perth Royal Infirmary, University of Dundee, UK
- 3Division of Maternal and Child Health Sciences, Children’s Asthma and Allergy Unit, Ninewells Hospital and Perth Royal Infirmary, University of Dundee, UK
- Correspondence to:
Professor B J Lipworth
Asthma and Allergy Research Group, Division of Medicine and Therapeutics, Ninewells Hospital, Dundee, UK;b.j.lipworth{at}dundee.ac.uk
- Received 23 January 2006
- Accepted 29 May 2006
- Published Online First 13 June 2006
Abstract
Background: The homozygous presence of the arginine-16 variant of the β2 adrenoceptor gene ADRB2 reverses the benefits from the regular use of short acting β2 agonists in asthmatic adults compared with the homozygous glycine-16 genotype. We studied the effect of this polymorphic variation on asthma exacerbations in children and young adults and its relation to long acting β2 agonists.
Methods: A cross-sectional survey was undertaken using electronic records, direct interviews, and genotype determination of position 16 and 27 of the ADRB2 gene in DNA from mouthwash samples of 546 children and young asthmatics attending paediatric and young adult asthma clinics in Tayside, Scotland during 2004–5. The primary outcome measure was asthma exacerbations over the previous 6 months.
Results: There was an increased hazard of asthma exacerbations across all treatment steps of the British Thoracic Society (BTS) asthma guidelines when the homozygous genotypes Arg/Arg and Gly/Gly were compared (OR 2.05, 95% CI 1.19 to 3.53, p = 0.010), particularly in patients treated with salmeterol (OR 3.40, 95% CI 1.19 to 9.40, p = 0.022). The Glu27Gln polymorphism had no significant effect on asthma exacerbations in any treatment group.
Conclusions: The arginine-16 genotype of ADRB2 predisposes to exacerbations in asthmatic children and young adults, particularly in those exposed to regular salmeterol. This may be explained by genotype selective salmeterol induced downregulation and impaired receptor coupling, and associated subsensitivity of the response.
Footnotes
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Published Online First 13 June 2006
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CNAP and SM had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: CNAP, SM, BJL. Acquisition of data: IM, TI, DFM. Genotyping: SL. Analysis and interpretation of data: CNAP, SM, BJL. Drafting of manuscript: CNAP, SM, BJL. Critical revision of the manuscript for important intellectual content: CNAP, BJL, SM. Statistical expertise: CNAP, TI. Supervision: CNAP, SM. All authors participated in the writing of the manuscript and have approved the final version for submission.
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Funding was provided by the Gannochy Trust (Perth, Scotland), Scottish Enterprises Tayside, and the Perth and Kinross Council. CNAP is supported by the Scottish Executive Genetic Health Initiative Award. The sponsors provided grant funding for operational costs of the project but did not participate in data collection, analysis, or the decision to publish.
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Competing interests: BJL and SM have accepted speaker’s fees, reimbursements for attending conferences, and funds for research from Merck Sharp and Dohme (UK) and GlaxoSmithKline (UK) in the past five years.
