title: Genetic variation in uncontrolled childhood asthma despite ICS treatment.
abstract: Genetic variation may partly explain asthma treatment response heterogeneity. We aimed to identify common and rare genetic variants associated with asthma that was not well controlled despite inhaled corticosteroid (ICS) treatment. Data of 110 children was collected in the Children Asthma Therapy Optimal trial. Associations of genetic variation with measures of lung function (FEV1%pred), airway hyperresponsiveness (AHR) to methacholine (Mch PD20) and treatment response outcomes were analyzed using the exome chip. The 17q12-21 locus (containing ORMDL3 and GSMDB) previously associated with childhood asthma was investigated separately. Single-nucleotide polymorphisms (SNPs) in the 17q12-21 locus were found nominally associated with the outcomes. The strongest association in this region was found for rs72821893 in KRT25 with FEV1%pred (P=3.75*10(-5)), Mch PD20 (P=0.00095) and Mch PD20-based treatment outcome (P=0.006). No novel single SNPs or burden tests were significantly associated with the outcomes. The 17q12-21 region was associated with FEV1%pred and AHR, and additionally with ICS treatment response.
authors.affiliation: Division of Pharmacoepidemiology & Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.|Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Leusink
authors.affiliation: Division of Pharmacoepidemiology & Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.|Department of Respiratory Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: S J H
authors.initials: SJ
authors.lastname: Vijverberg
authors.affiliation: Department of Respiratory Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: L
authors.initials: L
authors.lastname: Koenderman
authors.affiliation: Division of Pharmacoepidemiology & Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
authors.forename: J A M
authors.initials: JA
authors.lastname: Raaijmakers
authors.affiliation: Department of Pediatric Respiratory Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: J C
authors.initials: JC
authors.lastname: de Jongste
authors.affiliation: Department of Respiratory Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: P J
authors.initials: PJ
authors.lastname: Sterk
authors.affiliation: Department of Pediatric Pulmonology and Pediatric Allergology, Beatrix Children's Hospital, Groningen Research Institute for Asthma and COPD, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: E J
authors.initials: EJ
authors.lastname: Duiverman
authors.affiliation: Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: N C
authors.initials: NC
authors.lastname: Onland-Moret
authors.affiliation: Department of Pulmonology, Groningen Research Institute for Asthma and COPD, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: D S
authors.initials: DS
authors.lastname: Postma
authors.affiliation: Division of Pharmacoepidemiology & Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: de Boer
authors.affiliation: Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.|Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: P I W
authors.initials: PI
authors.lastname: de Bakker
authors.affiliation: Department of Pediatric Pulmonology and Pediatric Allergology, Beatrix Children's Hospital, Groningen Research Institute for Asthma and COPD, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: G H
authors.initials: GH
authors.lastname: Koppelman
authors.affiliation: Division of Pharmacoepidemiology & Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
authors.forename: A H
authors.initials: AH
authors.lastname: Maitland-van der Zee
mesh_terms: D000305:Adrenal Cortex Hormones / Q000627:therapeutic use*; D018927:Anti-Asthmatic Agents / Q000627:therapeutic use*; D001249:Asthma / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology; D002648:Child; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies; D056426:Genetic Loci; D006801:Humans; D008297:Male; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D017211:Treatment Failure
chemical_list: D000305:Adrenal Cortex Hormones; D018927:Anti-Asthmatic Agents