title: Vanin-1 expression and methylation discriminate pediatric asthma corticosteroid treatment response.
abstract: BACKGROUND
  There is considerable heterogeneity in asthma treatment response.
  
  
  OBJECTIVE
  We sought to identify biomarkers of corticosteroid treatment response in children with asthma and evaluate the utility and mechanistic basis of these biomarkers.
  
  
  METHODS
  Children (5-18 years) presenting to the emergency department with an acute asthma exacerbation were recruited and followed during hospitalization. Nasal epithelial cells were collected on presentation to the emergency department (T0) and 18 to 24 hours later (T1), and T1/T0 gene expression ratios were analyzed to identify genes associated with good and poor corticosteroid treatment response phenotypes. The utility of these genes in discriminating between systemic corticosteroid treatment response groups was then tested prospectively in a new cohort of patients. A gene candidate (vanin-1 [VNN1]) that consistently distinguished good versus poor response phenotypes was further studied in an experimental asthma model, and VNN1 promoter methylation was measured by means of bisulfite pyrosequencing in patients.
  
  
  RESULTS
  VNN1 mRNA expression changes were associated with systemic corticosteroid treatment response in children with acute asthma, and VNN1 was required for optimal response to corticosteroid treatment in an experimental asthma model. A CpG site within the VNN1 promoter was differentially methylated between good versus poor treatment response groups, and methylation at this site correlated with VNN1 mRNA expression.
  
  
  CONCLUSIONS
  We have identified a biological basis for poor corticosteroid treatment response that can be used to distinguish a subgroup of asthmatic children who respond poorly to systemic corticosteroid treatment. VNN1 contributes to corticosteroid responsiveness, and changes in VNN1 nasal epithelial mRNA expression and VNN1 promoter methylation might be clinically useful biomarkers of treatment response in asthmatic children.
authors.affiliation: Division of Asthma Research, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio.
authors.forename: Chang
authors.initials: C
authors.lastname: Xiao
authors.affiliation: Division of Asthma Research, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio.
authors.forename: Jocelyn M
authors.initials: JM
authors.lastname: Biagini Myers
authors.affiliation: Division of Asthma Research, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio.
authors.forename: Hong
authors.initials: H
authors.lastname: Ji
authors.affiliation: Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio.
authors.forename: Kelly
authors.initials: K
authors.lastname: Metz
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio.
authors.forename: Lisa J
authors.initials: LJ
authors.lastname: Martin
authors.affiliation: Division of Asthma Research, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio.
authors.forename: Mark
authors.initials: M
authors.lastname: Lindsey
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio.
authors.forename: Hua
authors.initials: H
authors.lastname: He
authors.affiliation: Division of Asthma Research, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio.
authors.forename: Racheal
authors.initials: R
authors.lastname: Powers
authors.affiliation: Division of Asthma Research, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio.
authors.forename: Ashley
authors.initials: A
authors.lastname: Ulm
authors.affiliation: Division of Asthma Research, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio.
authors.forename: Brandy
authors.initials: B
authors.lastname: Ruff
authors.affiliation: Division of Asthma Research, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio.
authors.forename: Mark B
authors.initials: MB
authors.lastname: Ericksen
authors.affiliation: Division of Asthma Research, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio.
authors.forename: Hari K
authors.initials: HK
authors.lastname: Somineni
authors.affiliation: Division of Hospital Medicine, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Simmons
authors.affiliation: Division of Emergency Medicine, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio.
authors.forename: Richard T
authors.initials: RT
authors.lastname: Strait
authors.affiliation: Division of Pulmonary Medicine, and the Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio.
authors.forename: Carolyn M
authors.initials: CM
authors.lastname: Kercsmar
authors.affiliation: Division of Asthma Research, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio. Electronic address: Gurjit.Hershey@cchmc.org.
authors.forename: Gurjit K
authors.initials: GK
authors.lastname: Khurana Hershey
mesh_terms: D000293:Adolescent; D000305:Adrenal Cortex Hormones / Q000627:therapeutic use*; D000581:Amidohydrolases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001249:Asthma / Q000175:diagnosis / Q000188:drug therapy*; D054316:Biomarkers, Pharmacological / Q000378:metabolism*; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D019175:DNA Methylation; D018450:Disease Progression; D004632:Emergency Medical Services; D005260:Female; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006760:Hospitalization; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D023421:Models, Animal; D009297:Nasal Mucosa / Q000502:physiology*; D011446:Prospective Studies; D016896:Treatment Outcome
chemical_list: D000305:Adrenal Cortex Hormones; D054316:Biomarkers, Pharmacological; D058851:GPI-Linked Proteins; D000581:Amidohydrolases; C022314:pantetheinase
keywords: Childhood asthma; biomarker; phenotype; treatment response; vanin-1