Arg16 ADRB2 genotype increases the risk of asthma exacerbation in children with a reported use of long-acting β2-agonists: results of the pacman cohort
Abstract
Background: Current evidence suggests that asthma patients with the ADRB2 Arg16 genotype have a poorer response to long-acting β2-agonists (LABA), but the results remain inconsistent. Aim: This study assessed the association between Arg16 variants and treatment outcome in children treated with inhaled corticosteroids (ICS) and LABA. Materials & methods:ADRB2 Arg16 was genotyped in 597 children (4–12 years of age) participating in the PACMAN cohort study. A questionnaire was used to assess asthma control, frequency of asthma-related emergency department visits and use of oral corticosteroids in the past year. Results: Arg/Arg carriers with a reported use of ICS and LABA had an increased risk of oral corticosteroid use (odds ratio: 14.9; 95% CI: 1.59–140.1) and emergency department visits in the past year (odds ratio: 11.9; 95% CI: 1.22–115.8) compared to Gly/Gly carriers. This effect was not observed in Arg/Arg genotype carriers reporting ICS use only. Conclusion: Children who are homozygous for ADRB2 Arg16 have an increased risk of exacerbations when treated with combined LABA and ICS.
Original submitted 4 September 2013; Revision submitted 27 September 2013
Papers of special note have been highlighted as: ▪ of interest ▪▪ of considerable interest
References
- 1 Braman SS. The global burden of asthma. Chest130(1 Suppl.),4S–12S (2006).
- 2 Pascual RM, Bleecker ER. Pharmacogenetics of asthma. Curr. Opin. Pharmacol.10(3),226–235 (2010).
- 3 Lipworth BJ, Basu K, Donald HP et al. Tailored second-line therapy in asthmatic children with the Arg16 genotype. Clin. Sci. (Lond.)124(8),521–528 (2013).▪▪ First randomized controlled trial to include only children who were homozygous for the Arg16 b2-receptor genotype in order to assess the response to montelukast or salmeterol as add-on treatments to inhaled corticosteroids.
- 4 Basu K, Palmer CN, Tavendale R, Lipworth BJ, Mukhopadhyay S. Adrenergic beta2-receptor genotype predisposes to exacerbations in steroid-treated asthmatic patients taking frequent albuterol or salmeterol. J. Allergy Clin. Immunol.124(6),1188–1194.e3 (2009).▪ Large observational study that assessed the relationship between Arg16 genotype and asthma exacerbation in 1182 young Scottish asthma patients.
- 5 Palmer CN, Lipworth BJ, Lee S, Ismail T, Macgregor DF, Mukhopadhyay S. Arginine-16 beta2 adrenoceptor genotype predisposes to exacerbations in young asthmatics taking regular salmeterol. Thorax61(11),940–944 (2006).
- 6 Wechsler ME, Lehman E, Lazarus SC et al. Beta-adrenergic receptor polymorphisms and response to salmeterol. Am. J. Respir. Crit. Care Med.173(5),519–526 (2006).
- 7 Taylor DR, Drazen JM, Herbison GP, Yandava CN, Hancox RJ, Town GI. Asthma exacerbations during long term beta agonist use: influence of beta2 adrenoceptor polymorphism. Thorax55(9),762–767 (2000).
- 8 Wechsler ME, Kunselman SJ, Chinchilli VM et al. Effect of beta2-adrenergic receptor polymorphism on response to longacting beta2 agonist in asthma (LARGE trial): a genotype-stratified, randomised, placebo-controlled, crossover trial. Lancet374(9703),1754–1764 (2009).
- 9 Bleecker ER, Nelson HS, Kraft M et al. Beta2-receptor polymorphisms in patients receiving salmeterol with or without fluticasone propionate. Am. J. Respir. Crit. Care Med.181(7),676–687 (2010).
- 10 Bleecker ER, Postma DS, Lawrance RM, Meyers DA, Ambrose HJ, Goldman M. Effect of ADRB2 polymorphisms on response to longacting beta2-agonist therapy: a pharmacogenetic analysis of two randomised studies. Lancet370(9605),2118–2125 (2007).▪ Pharmacogenetic post hoc analysis of two large randomized controlled trials of Arg16 and treatment response to long-acting b2-agonists.
- 11 Bleecker ER, Yancey SW, Baitinger LA et al. Salmeterol response is not affected by beta2-adrenergic receptor genotype in subjects with persistent asthma. J. Allergy Clin. Immunol.118(4),809–816 (2006).
- 12 Koster ES, Raaijmakers JA, Koppelman GH et al. Pharmacogenetics of anti-inflammatory treatment in children with asthma: rationale and design of the PACMAN cohort. Pharmacogenomics10(8),1351–1361 (2009).
- 13 Juniper EF, Svensson K, Mork AC, Stahl E. Measurement properties and interpretation of three shortened versions of the asthma control questionnaire. Respir. Med.99(5),553–558 (2005).
- 14 Juniper EF, Bousquet J, Abetz L, Bateman ED; GOAL Committee. Identifying ‘well-controlled’ and ‘not well-controlled’ asthma using the asthma control questionnaire. Respir. Med.100(4),616–621 (2006).
- 15 Giubergia V, Gravina L, Castanos C, Chertkoff L. Influence of beta2-adrenergic receptor polymorphisms on asthma exacerbation in children with severe asthma regularly receiving salmeterol. Ann. Allergy Asthma Immunol.110(3),156–160 (2013).
- 16 Turner SW, Khoo SK, Laing IA et al. Beta2 adrenoceptor Arg16Gly polymorphism, airway responsiveness, lung function and asthma in infants and children. Clin. Exp. Allergy34(7),1043–1048 (2004).
- 17 Dijk FN, de Jongste JC, Postma DS, Koppelman GH. Genetics of onset of asthma. Curr. Opin. Allergy Clin. Immunol.13(2),193–202 (2013).
- 18 Wu AC, Tantisira K, Li L et al. Predictors of symptoms are different from predictors of severe exacerbations from asthma in children. Chest140(1),100–107 (2011).
- 19 Israel E, Chinchilli VM, Ford JG et al. Use of regularly scheduled albuterol treatment in asthma: genotype-stratified, randomised, placebo-controlled cross-over trial. Lancet364(9444),1505–1512 (2004).
- 20 Hall IP, Blakey JD, Al Balushi KA et al. Beta2-adrenoceptor polymorphisms and asthma from childhood to middle age in the British 1958 birth cohort: a genetic association study. Lancet368(9537),771–779 (2006).
