The arginine-16 beta 2 adrenoceptor genotype predisposes to exacerbations in young asthmatics taking regular salmeterol

Colin N.A Palmer ¹, Brian J Lipworth ^1*, Simon Lee ¹, Tahmina Ismail ¹, Donald F Macgregor ¹ and Somnath Mukhopadhyay ¹

¹ University of Dundee, United Kingdom

^* To whom correspondence should be addressed. E-mail: b.j.lipworth{at}dundee.ac.uk.

Accepted 29 May 2006

Abstract

Background: The homozygous presence of the arginine-16 variant of the 2-adrenoceptor gene, ADRB2, reverses the benefits from the regular use of short-acting 2-agonists in asthmatic adults as compared to 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 2-agonists.

Method: Cross-sectional survey using electronic records, direct interviews, genotype determination of position 16 and 27 of the ADRB2 gene in DNA from mouthwash samples for 546 children and young asthmatics attending paediatric and young adult asthma clinics in Tayside, Scotland over 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 comparing the homozygous genotypes Arg/Arg vs Gly/Gly (OR 2.05, 95%CI = 1.19-3.53, p=0.010). This genotypic hazard was largely in the salmeterol-treated patients when comparing Arg/Arg16 vs Gly/Gly16 (OR = 3.40, 95% CI = 1.19-9.40, 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 down regulation and impaired receptor coupling, and associated subsensitivity of response.

Keywords: asthma, beta 2 agonist, polymorphism

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