Arginine-16  2 adrenoceptor genotype predisposes to exacerbations in young asthmatics taking regular salmeterol

Abstract

Background: The homozygous presence of the arginine-16 variant of the b 2 adrenoceptor gene ADRB2 reverses the benefits from the regular use of short acting b 2 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 b 2 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.

Filaggrin null mutations are associated with increased asthma exacerbations in children and young adults

“…Using this and other measurement tools for quantifying risk, other forms of genetic variation, such as in the b 2 adrenergic receptor gene, have been shown to influence the likelihood of asthma exacerbations, possibly through an interaction with pharmacological treatments (36)(37)(38). We predict that the study of genetic variation in relation to clinical outcomes in asthma will further explain underlying mechanisms for this disease, identify at-risk populations for susceptibility, severity and major lifeevents, define drug choice, and contribute overall to significantly improved management strategies for asthma within 5-10 yearsÕ time.…”

Pharmacogenetics of Asthma

“…Recent studies reveal, that children and adolescent asthmatics with the Arg16 genotype suffer from asthma exacerbations more frequently than the Gly16 subpopulation (OR 2.05, 95% CI 1.19 to 3.53, p=0.010). This genotype-exacerbation correlation significantly increases after salmeterol treatment (OR 3.40, 95% CI 1.19 to 9.40, p=0.022) (Palmer et al, 2006). Other studies confirm the conclusion that risk of asthma exacerbation in the Arg16 group rises with higher doses and more frequent use of 2-agonists.…”

“…Some patients treated with salmeterol, experienced rare but severe asthma exacerbations (Nelson et al, 2006). Further investigation suggested a dependence between Arg16 genotype and faster decline of lung parameters (FEV1) after LABA application (Nelson et al, 2006;Wechsler et al, 2006;Lee et al, 2004;Palmer et al, 2006). A good example is a study of Wechsler and co-workers comparing salmeterol response in individuals with asthma homozygous for arginine (Arg16) with glycine homozygous (Gly16) group of patients.…”

Realizing Personalized Medicine in Asthmatic Children Requires Large-Scale Collaboration

“…These patterns may influence response to anti-inflammatory treatment. Furthermore, clinical trials in asthmatic adults could not demonstrate a modifying effect of ADRB2 Arg16 genotype on LABA treatment outcome [14,15], suggesting that the effect of ADRB2 might be restricted to LABA response in childhood-onset disease [16,17]. In addition, a recent GWAS analysis identified a SNP influencing FBXL7 expression to be associated with improvement in asthma symptoms in response to ICS [18].…”