title: ST13 polymorphisms and their effect on exacerbations in steroid-treated asthmatic children and young adults.
abstract: BACKGROUND
  The clinical response to inhaled corticosteroids (ICS) is associated with single nucleotide polymorphisms (SNPs) in various genes. This study aimed to relate variations in genes in the steroid pathway and asthma susceptibility genes to exacerbations in children and young adults treated with ICS.
  
  
  METHODS
  We performed a meta-analysis of three cohort studies: Pharmacogenetics of Asthma Medication in Children: Medication with Anti-Inflammatory effects (n = 357, age: 4-12 years, the Netherlands), BREATHE (n = 820, age: 3-22 years, UK) and Paediatric Asthma Gene Environment Study (n = 391, age: 2-16 years, UK). Seventeen genes were selected based on a role in the glucocorticoid signalling pathway or a reported association with asthma. Two outcome parameters were used to reflect exacerbations: hospital visits and oral corticosteroid (OCS) use in the previous year. The most significant associations were tested in three independent validation cohorts; the Childhood Asthma Management Programme (clinical trial, n = 172, age: 5-12 years, USA), the Genes- environment and Mixture in Latino Americans II- study (n = 745, age: 8-21, USA) and the Pharmacogenetics of adrenal suppression cohort (n = 391, age: 5-18, UK) to test the robustness of the findings. Finally, all results were meta-analysed.
  
  
  RESULTS
  Two SNPs in ST13 (rs138335 and rs138337), but not in the other genes, were associated at a nominal level with an increased risk of exacerbations in asthmatics using ICS in the three cohorts studied. In a meta-analysis of all six studies, ST13 rs138335 remained associated with an increased risk of asthma-related hospital visits and OCS use in the previous year; OR = 1.22 (P = 0.013) and OR = 1.22 (P = 0.0017), respectively.
  
  
  CONCLUSIONS
  A novel susceptibility gene, ST13, coding for a cochaperone of the glucocorticoid receptor, is associated with exacerbations in asthmatic children and young adults despite their ICS use. Genetic variation in the glucocorticoid signalling pathway may contribute to the interindividual variability in clinical response to ICS treatment in children and young adults.
authors.affiliation: Division of Pharmacoepidemiology & Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences (UIPS), Faculty of Science, Utrecht University, Utrecht, The Netherlands.|Department of Respiratory Medicine, University Medical Centre Utrecht, Utrecht, The Netherlands.
authors.forename: S J H
authors.initials: SJ
authors.lastname: Vijverberg
authors.affiliation: Division of Pharmacoepidemiology & Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences (UIPS), Faculty of Science, Utrecht University, Utrecht, The Netherlands.
authors.forename: E S
authors.initials: ES
authors.lastname: Koster
authors.affiliation: Population Pharmacogenetics Group, Biomedical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK.
authors.forename: R
authors.initials: R
authors.lastname: Tavendale
authors.affiliation: Division of Pharmacoepidemiology & Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences (UIPS), Faculty of Science, Utrecht University, Utrecht, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Leusink
authors.affiliation: Department of Respiratory Medicine, University Medical Centre 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 (UIPS), Faculty of Science, Utrecht University, Utrecht, The Netherlands.
authors.forename: J A M
authors.initials: JA
authors.lastname: Raaijmakers
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: Department of Paediatric Pulmonology and Paediatric 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: Department of Child Health, University of Aberdeen, Aberdeen, UK.
authors.forename: S W
authors.initials: SW
authors.lastname: Turner
authors.affiliation: Population Pharmacogenetics Group, Biomedical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK.|Academic Department of Paediatrics, Royal Alexandra Children's Hospital, Brighton and Sussex Medical School, Brighton, UK.
authors.forename: S
authors.initials: S
authors.lastname: Mukhopadhyay
authors.affiliation: Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.|Sainte- Justine University Health Center, Montreal, Quebec, Canada.
authors.forename: S M
authors.initials: SM
authors.lastname: Tse
authors.affiliation: Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: K G
authors.initials: KG
authors.lastname: Tantisira
authors.affiliation: Department of Women's and Children's Health, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
authors.forename: D B
authors.initials: DB
authors.lastname: Hawcutt
authors.affiliation: Department of Biostatistics, University of Liverpool, Liverpool, UK.
authors.forename: B
authors.initials: B
authors.lastname: Francis
authors.affiliation: Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
authors.forename: M
authors.initials: M
authors.lastname: Pirmohamed
authors.affiliation: Department of Medicine, University of California, San Francisco, CA, USA.|CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Pino-Yanes
authors.affiliation: Department of Medicine, University of California, San Francisco, CA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Eng
authors.affiliation: Department of Medicine, University of California, San Francisco, CA, USA.|Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA, USA.
authors.forename: E G
authors.initials: EG
authors.lastname: Burchard
authors.affiliation: Population Pharmacogenetics Group, Biomedical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK.
authors.forename: C N A
authors.initials: CN
authors.lastname: Palmer
authors.affiliation: Division of Pharmacoepidemiology & Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences (UIPS), Faculty of Science, Utrecht University, Utrecht, The Netherlands.
authors.forename: A H
authors.initials: AH
authors.lastname: Maitland-van der Zee
mesh_terms: D000293:Adolescent; D000305:Adrenal Cortex Hormones / Q000008:administration & dosage / Q000627:therapeutic use*; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001249:Asthma / Q000188:drug therapy* / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D016896:Treatment Outcome; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D055815:Young Adult; D018832:Molecular Chaperones
chemical_list: D000305:Adrenal Cortex Hormones; D018927:Anti-Asthmatic Agents; D002352:Carrier Proteins; D025521:Tumor Suppressor Proteins; C101119:ST13 protein, human; D018832:Molecular Chaperones
keywords: ST13; childhood asthma; corticosteroids; exacerbations; pharmacogenomics