Meta-Analysis

. 2025 Apr;80(4):1006-1014.

doi: 10.1111/all.16438. Epub 2024 Dec 26.

Genotype-Guided Asthma Treatment Reduces Exacerbations in Children: Meta-Analysis of Two Randomized Control Trials

Elise M A Slob^{1

2

3}, Susanne J H Vijverberg¹, Tom Ruffles^{4

5}, Lieke C E Noij^{1

6}, Jacqueline Biermann⁷, Alwin F J Brouwer⁸, Kristel van den Brink⁹, Annette de Bruin-Kok¹⁰, Bart E Van Ewijk¹⁰, Eric Haarman⁶, Sanne C Hammer¹¹, Simone Hashimoto^{1

6}, Fiona Hogarth¹², Christina J Jones¹³, Arvid W A Kamps⁷, Elin T G Kersten^{14

15}, Ismé de Kleer¹⁶, Brian J Lipworth¹⁷, Roberta Littleford¹⁸, Marieke Mérelle⁹, Alexander Moeller¹⁹, Colin N A Palmer²⁰, Kristina Pilvinyte¹², Niels W Rutjes⁶, Ron H N van Schaik²¹, Helen E Smith²², Roger Tavendale²⁰, Suzanne W J Terheggen-Lagro⁶, Steve Turner²³, Jos W R Twisk²⁴, Anja Vaessen-Verberne¹¹, Mariël Verwaal²⁵, Tjalling de Vries²⁶, Judit Wesseling²⁷, Mariëlle W Pijnenburg²⁸, Gerard H Koppelman^{14

15}, Somnath Mukhopadhyay^{4

5}, Anke H Maitland-van der Zee^{1

6}

Affiliations

¹ Department of Pulmonary Medicine, AmsterdamUMC, University of Amsterdam, Amsterdam, The Netherlands.
² Department of Clinical Pharmacy, Haaglanden Medical Center, The Hague, The Netherlands.
³ Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands.
⁴ Academic Department of Paediatrics, Royal Alexandra Children's Hospital, University Hospitals Sussex NHS Foundation Trust, Brighton, UK.
⁵ Brighton and Sussex Medical School, Brighton, UK.
⁶ Department of Pediatric Pulmonology & Allergy, AmsterdamUMC, Emma Children's Hospital, Amsterdam, The Netherlands.
⁷ Department of Paediatrics, Martini Hospital, Groningen, The Netherlands.
⁸ Department of Paediatrics, Nij Smellinghe Hospital, Drachten, The Netherlands.
⁹ Department of Pediatrics, Spaarne Hospital, Hoofddorp, The Netherlands.
¹⁰ Deptartment of Paediatrics, Tergooi MC, Hilversum, The Netherlands.
¹¹ Deptartment of Paediatrics, Amphia Hospital, Breda, The Netherlands.
¹² Tayside Clinical Trials Unit, University of Dundee, Dundee, UK.
¹³ School of Psychology, Faculty of Health & Medical Sciences, University of Surrey, Guildford, UK.
¹⁴ Department of Pediatric Pulmonology & Allergology, Beatrix Children's Hospital, University Medical Center Groningen, Groningen, The Netherlands.
¹⁵ Groningen Research Institute on Asthma and COPD, University Medical Center Groningen, Groningen, The Netherlands.
¹⁶ Department of Paediatrics, Franciscus Gasthuis & Vlietland, Rotterdam, The Netherlands.
¹⁷ Scottish Centre for Respiratory Research, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK.
¹⁸ Clinical Trial Centre, The University of Queensland, Brisbane, Australia.
¹⁹ Department of Respiratory Medicine, University Children Hospital and University of Zürich, Zürich, Switzerland.
²⁰ Pat McPherson Centre for Pharmacogenetics and Pharmacogenomics, Division of Population Health and Genomics, School of Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, UK.
²¹ Department of Clinical Chemistry, Erasmus University Medical Center, Rotterdam, The Netherlands.
²² School of Medicine, Keele University, Keele, Staffordshire, UK.
²³ Women and Children's Division, NHS Grampian, Aberdeen, UK.
²⁴ Department of Epidemiology and Data Science, AmsterdamUMC, Amsterdam, The Netherlands.
²⁵ Department of Paediatrics, Maasstad Hospital, Rotterdam, The Netherlands.
²⁶ Department of Paediatrics, Medical Centre Leeuwarden, Leeuwarden, The Netherlands.
²⁷ Department of Paediatrics, Rijnstate Hospital, Arnhem, The Netherlands.
²⁸ Department of Pediatrics, Pediatric Pulmonology & Allergology, Erasmus Medical Center, Rotterdam, The Netherlands.

PMID: 39723595
PMCID: PMC11969299
DOI: 10.1111/all.16438

Meta-Analysis

Genotype-Guided Asthma Treatment Reduces Exacerbations in Children: Meta-Analysis of Two Randomized Control Trials

Elise M A Slob et al. Allergy. 2025 Apr.

. 2025 Apr;80(4):1006-1014.

doi: 10.1111/all.16438. Epub 2024 Dec 26.

Authors

Affiliations

¹ Department of Pulmonary Medicine, AmsterdamUMC, University of Amsterdam, Amsterdam, The Netherlands.
² Department of Clinical Pharmacy, Haaglanden Medical Center, The Hague, The Netherlands.
³ Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands.
⁴ Academic Department of Paediatrics, Royal Alexandra Children's Hospital, University Hospitals Sussex NHS Foundation Trust, Brighton, UK.
⁵ Brighton and Sussex Medical School, Brighton, UK.
⁶ Department of Pediatric Pulmonology & Allergy, AmsterdamUMC, Emma Children's Hospital, Amsterdam, The Netherlands.
⁷ Department of Paediatrics, Martini Hospital, Groningen, The Netherlands.
⁸ Department of Paediatrics, Nij Smellinghe Hospital, Drachten, The Netherlands.
⁹ Department of Pediatrics, Spaarne Hospital, Hoofddorp, The Netherlands.
¹⁰ Deptartment of Paediatrics, Tergooi MC, Hilversum, The Netherlands.
¹¹ Deptartment of Paediatrics, Amphia Hospital, Breda, The Netherlands.
¹² Tayside Clinical Trials Unit, University of Dundee, Dundee, UK.
¹³ School of Psychology, Faculty of Health & Medical Sciences, University of Surrey, Guildford, UK.
¹⁴ Department of Pediatric Pulmonology & Allergology, Beatrix Children's Hospital, University Medical Center Groningen, Groningen, The Netherlands.
¹⁵ Groningen Research Institute on Asthma and COPD, University Medical Center Groningen, Groningen, The Netherlands.
¹⁶ Department of Paediatrics, Franciscus Gasthuis & Vlietland, Rotterdam, The Netherlands.
¹⁷ Scottish Centre for Respiratory Research, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK.
¹⁸ Clinical Trial Centre, The University of Queensland, Brisbane, Australia.
¹⁹ Department of Respiratory Medicine, University Children Hospital and University of Zürich, Zürich, Switzerland.
²⁰ Pat McPherson Centre for Pharmacogenetics and Pharmacogenomics, Division of Population Health and Genomics, School of Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, UK.
²¹ Department of Clinical Chemistry, Erasmus University Medical Center, Rotterdam, The Netherlands.
²² School of Medicine, Keele University, Keele, Staffordshire, UK.
²³ Women and Children's Division, NHS Grampian, Aberdeen, UK.
²⁴ Department of Epidemiology and Data Science, AmsterdamUMC, Amsterdam, The Netherlands.
²⁵ Department of Paediatrics, Maasstad Hospital, Rotterdam, The Netherlands.
²⁶ Department of Paediatrics, Medical Centre Leeuwarden, Leeuwarden, The Netherlands.
²⁷ Department of Paediatrics, Rijnstate Hospital, Arnhem, The Netherlands.
²⁸ Department of Pediatrics, Pediatric Pulmonology & Allergology, Erasmus Medical Center, Rotterdam, The Netherlands.

PMID: 39723595
PMCID: PMC11969299
DOI: 10.1111/all.16438

Abstract

Background: Long-acting beta2-agonists (LABA) in combination with inhaled corticosteroids (ICS) are commonly used to treat asthma, however, some children lack response to the addition of LABA. This might be partially due to the presence of the Arg16Gly polymorphism, encoded by rs1042713 G>A in the ADRB2 gene. Carrying the A allele (Arg16) at this variant has been associated with an increased risk of exacerbations despite LABA treatment. We investigated whether genotype-guided treatment improved asthma-related outcomes.

Methods: We conducted an individual participant data meta-analysis of two randomised controlled trials: PUFFIN (Dutch and Swiss 6-18 year-olds) and PACT (English and Scottish 12-18 year-olds). Children with uncontrolled asthma despite ICS who required a step-up in treatment were included. Participants were randomised to genotype-guided treatment or the control group with a follow-up of at least 6 months. Genotype-guided treatment consisted of adding LABA for children with ADRB2 Gly16/Gly16, whilst children with ADRB2 Arg16/Arg16 or Arg16/Gly16 were treated with double dose ICS (PUFFIN) or add-on montelukast (PACT). The primary outcome was a change in asthma control; secondary outcomes included exacerbation rate and time to exacerbation. Repeated measures mixed models and Cox regression were used.

Results: Fifty-nine out of 102 (PUFFIN) and 59 out of 91 (PACT) children had at least one Arg (A allele). Amongst all 193 children, no difference was observed in asthma control between the study groups. However, genotype-guided treatment resulted in lower asthma exacerbation rates (-0.08 (95%CI -0.16 to -0.00, p = 0.04)) compared to the control group.

Conclusion: Genotype-guided step-up treatment for children with uncontrolled asthma on ICS may lower asthma exacerbation rates and may be useful for personalising asthma care.

Keywords: ADRB2; asthma; long‐acting beta2‐agonist; paediatrics; pharmacogenetics.

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Conflict of interest statement

A.H.M.v.d.Z. is the PI of a public private consortium (P4O2 (Precision Medicine for More Oxygen)) sponsored by Health Holland involving many private partners that contribute in cash and/or in kind (AbbVie, Boehringer Ingelheim, Breathomix, Clear, Fluidda, Ortec Logiqcare, Olive, Philips, Quantib‐U, Smartfish, Clear, SODAQ, Thirona, Roche, TopMD, Novartis and RespiQ). A.H.M.v.d.Z. also reports funding from GSK, Boehringer Ingelheim, Vertex and Astra Zeneca. G.H.K. reports funding from the Lung Foundation Netherlands, ZON‐MW, Health Holland, European Union, TEVA the Netherlands, GSK, Vertex and participated in advisory boards of Astra Zeneca and Pure‐IMS (money to institution); his institution received compensation for invited lectures from Boehringer Ingelheim and Sanofi. S. Mukhopadhyay reports funding from the National Health Service, UK, National Institute of Health Research, UK, Action Medical Research charity, UK and Rockinghorse Children's Charity, UK. M.W.P. reports funding from Lung Foundation Netherlands, Zon‐MW, Sanofi, Novartis and Astra Zeneca. B.L. reports personal fees from Sandoz, AstraZeneca, Chiesi, Lupin and Cipla, E.M.A.S., E.T.G.K. and S.J.H.V. report funding from Lung Foundation Netherlands. M.V. participated in the revision of the Dutch asthma guideline in children (Dutch Association of Paediatrics) and is chairman of the foundation for nurse practitioners in paediatric lung diseases. C.J. reports research funding from the National Institute for Health Research, the Food Standards Agency Coeliac UK and honoraria from the National Institute for Health Research, Nutricia, Reckitt Benckiser, DBV Technologies and Allergy UK. T.R., L.N., R.H.N.v.S., A.F.J.B., A.A.P.H.V., S.C.H., E.G.H., B.v.E., H.E.S., K.P., F.H., S.W.J.T.‐L., R.L., J.W., T.d.V., J.B., I.d.K., C.N.A.P., R.T., A.d.B. and J.W.R.T. declare no conflicts of interest.

Figures

**FIGURE 1**
Flow chart of participant inclusion.

See this image and copyright information in PMC

Cited by

ADRB2 genotype-guided treatment for childhood asthma: Cost analysis of the PUFFIN and PACT trials.
Slob EMA, Frederix GWJ, Vijverberg SJH, Noij LCE, Ruffles T, Vasbinder EC, Mukhopadhyay S, van Schaik RHN, Kersten ETG, Pijnenburg MW, Koppelman GH, Maitland-van der Zee AH; PUFFIN and PACT investigators. Slob EMA, et al. Pediatr Allergy Immunol. 2025 Jun;36(6):e70113. doi: 10.1111/pai.70113. Pediatr Allergy Immunol. 2025. PMID: 40464075 Free PMC article. Clinical Trial.
Unveiling the Complexities of Pediatric Asthma Treatment: Evidence, Controversies, and Emerging Approaches.
Di Cicco ME, Peroni D, Marseglia GL, Licari A. Di Cicco ME, et al. Paediatr Drugs. 2025 Jul;27(4):393-404. doi: 10.1007/s40272-025-00694-6. Epub 2025 Mar 22. Paediatr Drugs. 2025. PMID: 40120047 Free PMC article. Review.

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Genotype-Guided Asthma Treatment Reduces Exacerbations in Children: Meta-Analysis of Two Randomized Control Trials

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Genotype-Guided Asthma Treatment Reduces Exacerbations in Children: Meta-Analysis of Two Randomized Control Trials

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