title: Childhood asthma is associated with mutations and gene expression differences of ORMDL genes that can interact.
abstract: BACKGROUND
  Genomewide association studies identified ORMDL3 as a plausible asthma candidate gene. ORMDL proteins regulate sphingolipid metabolism and ceramide homeostasis and participate in lymphocyte activation and eosinophil recruitment. Strong sequence homology between the three ORMDL genes and ORMDL protein conservation among different species suggest that they may have shared functions. We hypothesized that if single nucleotide polymorphisms (SNPs) in ORMDL3 alter its gene expression and play a role in asthma, variants in ORMDL1 and ORMDL2 might also be associated with asthma.
  
  
  METHODS
  Asthma associations of 44 genotyped SNPs were determined in at least 1303 subjects (651 asthmatics). ORMDL expression was evaluated in peripheral blood mononuclear cells (PBMC) from 55 subjects (eight asthmatics) before and after allergen stimulation, and in blood (n = 60, 5 asthmatics). Allele-specific cis-effects on ORMDL expression were assessed. Interactions between human ORMDL proteins were determined in living cells.
  
  
  RESULTS
  Sixteen SNPs in all three ORMDLs were associated with asthma (14 in ORMDL3). Baseline expression of ORMDL1 (P = 1.7 × 10(-6) ) and ORMDL2 (P = 4.9 × 10(-5) ) was significantly higher in PBMC from asthmatics, while induction of ORMDLs upon stimulation was stronger in nonasthmatics. Disease-associated alleles (rs8079416, rs4795405, rs3902920) alter ORMDL3 expression. ORMDL proteins formed homo- and heterooligomers and displayed similar patterns of interaction with SERCA2 and SPT1.
  
  
  CONCLUSIONS
  Polymorphisms in ORMDL genes are associated with asthma. Asthmatics exhibit increased ORMDL levels, suggesting that ORMDLs contribute to asthma. Formation of heterooligomers and similar interaction patterns with proteins involved in calcium homeostasis and sphingolipid metabolism could indicate shared biological roles of ORMDLs, influencing airway remodeling and hyperresponsiveness.
authors.affiliation: Department of Pediatric Pneumology and Allergy, University Children's Hospital Regensburg (KUNO), Regensburg, Germany.|Department of Pediatric Pneumology, Allergy and Neonatology, Hannover Medical School, Hannover, Germany.
authors.forename: A A
authors.initials: AA
authors.lastname: Toncheva
authors.affiliation: Department of Pediatric Pneumology, Allergy and Neonatology, Hannover Medical School, Hannover, Germany.
authors.forename: D P
authors.initials: DP
authors.lastname: Potaczek
authors.affiliation: Department of Pediatric Pneumology, Allergy and Neonatology, Hannover Medical School, Hannover, Germany.|Department of Pediatrics, National Jewish Health, Denver, CO, USA.
authors.forename: M
authors.initials: M
authors.lastname: Schedel
authors.affiliation: Department of Molecular Pediatrics, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: S W
authors.initials: SW
authors.lastname: Gersting
authors.affiliation: Department of Pediatric Pneumology and Allergy, University Children's Hospital Regensburg (KUNO), Regensburg, Germany.|Department of Pediatric Pneumology, Allergy and Neonatology, Hannover Medical School, Hannover, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Michel
authors.affiliation: Department of Pediatric Pneumology, Allergy and Neonatology, Hannover Medical School, Hannover, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Krajnov
authors.affiliation: Department of Pediatric Pneumology and Allergy, University Children's Hospital Regensburg (KUNO), Regensburg, Germany.
authors.forename: V D
authors.initials: VD
authors.lastname: Gaertner
authors.affiliation: Department of Molecular Pediatrics, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: J M
authors.initials: JM
authors.lastname: Klingbeil
authors.affiliation: Research Unit of Molecular Epidemiology, Helmholtz Zentrum Munich, Neuherberg, Germany.|Hannover Unified Biobank, Hannover Medical School, Hannover, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Illig
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University Kiel, Kiel, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Franke
authors.affiliation: Department of Clinical Airway Research, Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany.|Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Winkler
authors.affiliation: Department of Clinical Airway Research, Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany.|Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany.
authors.forename: J M
authors.initials: JM
authors.lastname: Hohlfeld
authors.affiliation: University Children's Hospital, Technical University Dresden, Dresden, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Vogelberg
authors.affiliation: Research Institute for the Prevention of Allergic Diseases, Children's Department, Marien-Hospital, Wesel, Germany.
authors.forename: A
authors.initials: A
authors.lastname: von Berg
authors.affiliation: Department of Experimental Pneumology, Ruhr-University, Bochum, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Bufe
authors.affiliation: University Children's Hospital, Albert Ludwigs University, Freiburg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Heinzmann
authors.affiliation: Kinder- und Jugendarztpraxis Laub, Rosenheim, Germany.
authors.forename: O
authors.initials: O
authors.lastname: Laub
authors.affiliation: University Children's Hospital, University of Cologne, Cologne, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Rietschel
authors.affiliation: Children's Department, University Teaching Hospital, Landeskrankenhaus Feldkirch, Feldkirch, Austria.
authors.forename: B
authors.initials: B
authors.lastname: Simma
authors.affiliation: Institute of Epidemiology and Medical Biometry, Ulm University, Ulm, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Genuneit
authors.affiliation: University Children's Hospital, University Medical Center Hamburg Eppendorf, Hamburg, Germany.
authors.forename: A C
authors.initials: AC
authors.lastname: Muntau
authors.affiliation: Department of Pediatric Pneumology and Allergy, University Children's Hospital Regensburg (KUNO), Regensburg, Germany.|Department of Pediatric Pneumology, Allergy and Neonatology, Hannover Medical School, Hannover, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Kabesch
mesh_terms: D000367:Age Factors; D000483:Alleles; D001249:Asthma / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D016022:Case-Control Studies; D002874:Chromosome Mapping; D004843:Epistasis, Genetic; D005260:Female; D005786:Gene Expression Regulation; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D005810:Multigene Family; D009154:Mutation; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding
chemical_list: D008565:Membrane Proteins; C464259:ORMDL1 protein, human; C464279:ORMDL2 protein, human; C464399:ORMDL3 protein, human
keywords: bioluminescence energy transfer; childhood asthma; peripheral blood mononuclear cells; protein-protein interaction; single nucleotide polymorphism