title: Transcriptome analysis of controlled and therapy-resistant childhood asthma reveals distinct gene expression profiles.
abstract: BACKGROUND
  Children with problematic severe asthma have poor disease control despite high doses of inhaled corticosteroids and additional therapy, leading to personal suffering, early deterioration of lung function, and significant consumption of health care resources. If no exacerbating factors, such as smoking or allergies, are found after extensive investigation, these children are given a diagnosis of therapy-resistant (or therapy-refractory) asthma (SA).
  
  
  OBJECTIVE
  We sought to deepen our understanding of childhood SA by analyzing gene expression and modeling the underlying regulatory transcription factor networks in peripheral blood leukocytes.
  
  
  METHODS
  Gene expression was analyzed by using Cap Analysis of Gene Expression in children with SA (n = 13), children with controlled persistent asthma (n = 15), and age-matched healthy control subjects (n = 9). Cap Analysis of Gene Expression sequencing detects the transcription start sites of known and novel mRNAs and noncoding RNAs.
  
  
  RESULTS
  Sample groups could be separated by hierarchical clustering on 1305 differentially expressed transcription start sites, including 816 known genes and several novel transcripts. Ten of 13 tested novel transcripts were validated by means of RT-PCR and Sanger sequencing. Expression of RAR-related orphan receptor A (RORA), which has been linked to asthma in genome-wide association studies, was significantly upregulated in patients with SA. Gene network modeling revealed decreased glucocorticoid receptor signaling and increased activity of the mitogen-activated protein kinase and Jun kinase cascades in patients with SA.
  
  
  CONCLUSIONS
  Circulating leukocytes from children with controlled asthma and those with SA have distinct gene expression profiles, demonstrating the possible development of specific molecular biomarkers and supporting the need for novel therapeutic approaches.
authors: Department of Biosciences and Nutrition and Center for Innovative Medicine (CIMED), Karolinska Institutet, Stockholm, Sweden.
authors: Helena
authors: H
authors: Persson
authors: Omics Science Center,§ RIKEN Yokohama Institute, Yokohama, Japan; Division of Genomic Technologies, RIKEN Center for Life Science Technologies, Yokohama, Japan.
authors: Andrew T
authors: AT
authors: Kwon
authors: Omics Science Center,§ RIKEN Yokohama Institute, Yokohama, Japan; Division of Genomic Technologies, RIKEN Center for Life Science Technologies, Yokohama, Japan.
authors: Jordan A
authors: JA
authors: Ramilowski
authors: Unit of Computational Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
authors: Gilad
authors: G
authors: Silberberg
authors: Department of Biosciences and Nutrition and Center for Innovative Medicine (CIMED), Karolinska Institutet, Stockholm, Sweden; Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden.
authors: Cilla
authors: C
authors: Söderhäll
authors: Department of Biosciences and Nutrition and Center for Innovative Medicine (CIMED), Karolinska Institutet, Stockholm, Sweden.
authors: Christina
authors: C
authors: Orsmark-Pietras
authors: Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden; Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden; Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
authors: Björn
authors: B
authors: Nordlund
authors: Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden; Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden; Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
authors: Jon R
authors: JR
authors: Konradsen
authors: Omics Science Center,§ RIKEN Yokohama Institute, Yokohama, Japan; Division of Genomic Technologies, RIKEN Center for Life Science Technologies, Yokohama, Japan.
authors: Michiel J L
authors: MJ
authors: de Hoon
authors: Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden; Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; Sachs' Children's Hospital, Stockholm, Sweden.
authors: Erik
authors: E
authors: Melén
authors: Omics Science Center,§ RIKEN Yokohama Institute, Yokohama, Japan; Preventive Medicine and Diagnosis Innovation Program, RIKEN Research Cluster for Innovation, Wako, Japan.
authors: Yoshihide
authors: Y
authors: Hayashizaki
authors: Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden; Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden; Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
authors: Gunilla
authors: G
authors: Hedlin
authors: Department of Biosciences and Nutrition and Center for Innovative Medicine (CIMED), Karolinska Institutet, Stockholm, Sweden; Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden; Folkhälsan Institute of Genetics, Helsinki, Finland; Research Programs Unit, University of Helsinki, Helsinki, Finland. Electronic address: juha.kere@ki.se.
authors: Juha
authors: J
authors: Kere
authors: Department of Biosciences and Nutrition and Center for Innovative Medicine (CIMED), Karolinska Institutet, Stockholm, Sweden; Omics Science Center,§ RIKEN Yokohama Institute, Yokohama, Japan; Division of Genomic Technologies, RIKEN Center for Life Science Technologies, Yokohama, Japan.
authors: Carsten O
authors: CO
authors: Daub
mesh_terms: D000293:Adolescent; D001249:Asthma / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D004351:Drug Resistance / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D055106:Genome-Wide Association Study; D005938:Glucocorticoids / Q000627:therapeutic use*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics; D008297:Male; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1 / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics*; D011965:Receptors, Glucocorticoid / Q000235:genetics; D012720:Severity of Illness Index; D059467:Transcriptome
chemical_list: D005938:Glucocorticoids; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; D012333:RNA, Messenger; C539738:RORA protein, human; D011965:Receptors, Glucocorticoid; D048031:JNK Mitogen-Activated Protein Kinases
keywords: Therapy-resistant asthma; childhood asthma; long noncoding RNA; peripheral blood leukocytes; transcriptome