Elise M A Slob1, Susanne J H Vijverberg1, Colin N A Palmer2, Zulfan Zazuli1,3, Niloufar Farzan1, Nadia M B Oliveri1, Mariëlle W Pijnenburg4, Gerard H Koppelman5,6, Anke H Maitland-van der Zee1. 1. Department of Respiratory Medicine, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands. 2. Population Pharmacogenetics Group, Biomedical Research Centre, University of Dundee, Dundee, UK. 3. Department of Pharmacology-Clinical Pharmacy, School of Pharmacy, Bandung Institute of Technology, Bandung, Indonesia. 4. Department of Paediatrics, Paediatric Pulmonology & Allergology, Erasmus Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands. 5. Department of Paediatric, Pulmonology & Paediatric Allergology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. 6. Groningen Research Institute for Asthma & COPD (GRIAC), University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Abstract
BACKGROUND: Long-acting beta2-agonists (LABA) are recommended in asthma therapy; however, not all asthma patients respond well to LABA. We performed a systematic review on genetic variants associated with LABA response in patients with asthma. METHODS: Articles published until April 2017 were searched by two authors using PubMed and EMBASE. Pharmacogenetic studies in patients with asthma and LABA response as an outcome were included. RESULTS: In total, 33 studies were included in this systematic review; eight focused on children (n = 6051). Nineteen studies were clinical trials, while 14 were observational studies. Studies used different outcomes to define LABA response, for example, lung function measurements (FEV1 , PEF, MMEF, FVC), exacerbations, quality of life, and asthma symptoms. Most studies (n = 30) focused on the ADRB2 gene, encoding the beta2-adrenergic receptor. Thirty studies (n = 14 874) addressed ADRB2 rs1042713, 7 ADRB2 rs1042714 (n = 1629), and 3 ADRB2 rs1800888 (n = 1892). The association of ADRB2 rs1042713 and rs1800888 with LABA response heterogeneity was successfully replicated. Other variants were only studied in three studies but not replicated. One study focused on the ADCY9 gene. Five studies and a meta-analysis found an increased risk of exacerbations in pediatrics using LABA carrying one or two A alleles (OR 1.52 [1.17; 1.99]). These results were not confirmed in adults. CONCLUSIONS: ADRB2 rs1042713 variant is most consistently associated with response to LABA in children but not adults. To assess the clinical value of ADRB2 rs1042713 in children with asthma using LABA, a randomized clinical trial with well-defined outcomes is needed.
BACKGROUND: Long-acting beta2-agonists (LABA) are recommended in asthma therapy; however, not all asthmapatients respond well to LABA. We performed a systematic review on genetic variants associated with LABA response in patients with asthma. METHODS: Articles published until April 2017 were searched by two authors using PubMed and EMBASE. Pharmacogenetic studies in patients with asthma and LABA response as an outcome were included. RESULTS: In total, 33 studies were included in this systematic review; eight focused on children (n = 6051). Nineteen studies were clinical trials, while 14 were observational studies. Studies used different outcomes to define LABA response, for example, lung function measurements (FEV1 , PEF, MMEF, FVC), exacerbations, quality of life, and asthma symptoms. Most studies (n = 30) focused on the ADRB2 gene, encoding the beta2-adrenergic receptor. Thirty studies (n = 14 874) addressed ADRB2rs1042713, 7 ADRB2rs1042714 (n = 1629), and 3 ADRB2rs1800888 (n = 1892). The association of ADRB2rs1042713 and rs1800888 with LABA response heterogeneity was successfully replicated. Other variants were only studied in three studies but not replicated. One study focused on the ADCY9 gene. Five studies and a meta-analysis found an increased risk of exacerbations in pediatrics using LABA carrying one or two A alleles (OR 1.52 [1.17; 1.99]). These results were not confirmed in adults. CONCLUSIONS:ADRB2rs1042713 variant is most consistently associated with response to LABA in children but not adults. To assess the clinical value of ADRB2rs1042713 in children with asthma using LABA, a randomized clinical trial with well-defined outcomes is needed.
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