ASTHMA

Arginine-16 ß₂ adrenoceptor genotype predisposes to exacerbations in young asthmatics taking regular salmeterol

C N A Palmer¹, B J Lipworth², S Lee¹, T Ismail³, D F Macgregor³ and S Mukhopadhyay³

¹ Population Pharmacogenetics Group, Biomedical Research Centre, University of Dundee, UK
² Division of Medicine and Therapeutics, Asthma and Allergy Unit, Ninewells Hospital and Perth Royal Infirmary, University of Dundee, UK
³ Division of Maternal and Child Health Sciences, Children’s Asthma and Allergy Unit, Ninewells Hospital and Perth Royal Infirmary, University of Dundee, UK

Correspondence to:
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

Background: The homozygous presence of the arginine-16 variant of the ß₂ adrenoceptor gene ADRB2 reverses the benefits from the regular use of short acting ß₂ 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 ß₂ 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.

Keywords: asthma; children; polymorphism; salmeterol; ADRB2

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