Asthma prescribing according to Arg16Gly beta-2 genotype: a randomised trial in adolescents

Abstract

IntroductionThe A allele of rs1042713 (Arg16 amino acid) in the beta-2 (β2) adrenoreceptor is associated with poor response to long-acting β2-agonist (LABA) in young people with asthma. Our aim was to assess whether the prescribing of second line controller with LABA or a leukotriene receptor antagonist (LTRA) according to Arg16Gly genotype would result in improvements in pediatric asthma-related quality of life questionnaire (PAQLQ).MethodsWe performed a pragmatic randomised controlled trial (RCT) via a primary care clinical research network covering England and Scotland. We enrolled participants aged 12–18 years with asthma taking inhaled corticosteroids. A total of 241 participants (mean (sd) age 14.7 years (1.91)) were randomised (1:1) to receive personalised care (genotype directed prescribing) or standard guideline care. Following 4-week run-in participants were followed for 12-months. The primary outcome measure was change in PAQLQ. Asthma control, asthma exacerbation frequency and healthcare utilisation were secondary outcomes.ResultsGenotype directed prescribing resulted in an improvement in PAQLQ compared to standard care 0.16, (95%CI 0.00–0.31; p=0.049), although this improvement was below the pre-determined clinical threshold of 0.25. The AA genotype was associated with a larger improvement in PAQLQ with personalised versus standard care 0.42, (95%CI 0.02–0.81; p=0.041).ConclusionThis is the first RCT demonstrating that genotype driven asthma prescribing is associated with a significant improvement in a clinical outcome compared to standard care. Adolescents with the AA homozygous genotype benefited most. The potential role of such β2-adrenoceptor genotype directed therapy in younger and more severe childhood asthma warrants further exploration.

When biology meets behaviour: can medication adherence mask the contribution of pharmacogenetic effects in asthma?

“…We acknowledge that theophylline has a narrower therapeutic interval compared to LABAs, yet importantly the inhaled route of administration of LABAs is prone to incorrect use and non-adherence [4]. We wonder if patients were assessed for inhaler adherence and whether inhaler technique was checked and patients trained, as these factors may have explained the heterogeneity in response to treatment and possibly, as reported by the authors, a lower than expected effect observed for personalised medicine in their study [1].…”

“…We read the study of RUFFLES et al [1] with great interest. The authors undertook one of the first randomised controlled trials (RCTs) assessing the potential benefit of personalised prescription of bronchodilators according to Arg16Gly beta-2 genotype in adolescent patients with asthma.…”

“…The authors explored the effect of a pharmacogenetically guided stratified approach in a pragmatic setting, and we wonder whether "real-life" everyday factors may have influenced the pharmacological responses observed; in particular, adherence to therapy and inhaler technique. The authors describe that 60-80% of the variability in asthma drug response may be explained by genetics [1,2]. However, for some drugs, such as theophylline, it has been suggested that medication adherence may play a significant role in therapeutic response in contrast to genetics [3].…”

Genome‐wide association studies of exacerbations in children using long‐acting beta2‐agonists

“…This meta-GWAS contributes to knowledge of pharmacogenetic markers that can determine whether children experience exacerbations despite LABA use, potentially leading to further understanding of which patients would benefit from LABA treatment. Further investigation in future studies including data in children with exacerbations despite LABA use (such as the PACT trial 64 and the PUFFIN trial 65 once these are genome-wide genotyped) could potentially lead to more concise meta-GWAS results.…”

“…There may be ethnic differences in response to LABA, making it more complex to discover SNPs associated with exacerbations despite LABA use. Accordingly, the wide confidence intervals demonstrated for I 2 potentially indicate the presence of a reasonable amount of heterogeneity, which is presumably due to the limited number of studies included in the meta-analyses 63. Moreover, previous analysis of SAGE and GALA II genotyped with an array optimized for those admixed populations has revealed previously unknown SNPs for asthma exacerbations 55 despite ICS use.…”