title: PTTG1IP and MAML3, novel genomewide association study genes for severity of hyperresponsiveness in adult asthma.
abstract: BACKGROUND
  The severity of bronchial hyperresponsiveness (BHR) is a fundamental feature of asthma. The severity of BHR varies between asthmatics and is associated with lack of asthma control. The mechanisms underlying this trait are still unclear. This study aimed to identify genes associated with BHR severity, using a genomewide association study (GWAS) on the slope of BHR in adult asthmatics.
  
  
  METHODS
  We performed a GWAS on BHR severity in adult asthmatics from the Dutch Asthma GWAS cohort (n = 650), adjusting for smoking and inhaled corticosteroid use, and verified results in three other cohorts. Furthermore, we performed eQTL and co-expression analyses in lung tissue.
  
  
  RESULTS
  In the discovery cohort, one genomewide significant hit located in phosphodiesterase 4D, cAMP-specif (PDE4D) and 26 SNPs with P-values < 1*10-5were found. None of our findings replicated in adult and childhood replication cohorts jointly. In adult cohorts separately, rs1344110 in pituitary tumour-transforming 1 interacting protein (PTTG1IP) and rs345983 in Mastermind-like 3 (MAML3) replicated nominally; minor alleles of rs345983 and rs1344110 were associated with less severe BHR and higher lung tissue gene expression. PTTG1IP showed significant co-expression with pituitary tumour-transforming 1, the binding factor of PTTG1lP, and with vimentin and E-cadherin1. MAML3 co-expressed significantly with Mastermind-like 2 (MAML2), both involved in Notch signalling.
  
  
  CONCLUSIONS
  PTTG1IP and MAML3 are associated with BHR severity in adult asthma. The relevance of these genes is supported by the eQTL analyses and co-expression of PTTG1lP with vimentin and E-cadherin1, and MAML3 with MAML2.
authors.affiliation: Department of Pulmonary Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.|Groningen Research Institute for Asthma and COPD (GRIAC), University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: M A E
authors.initials: MA
authors.lastname: Nieuwenhuis
authors.affiliation: Groningen Research Institute for Asthma and COPD (GRIAC), University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.|Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: J M
authors.initials: JM
authors.lastname: Vonk
authors.affiliation: Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: B E
authors.initials: BE
authors.lastname: Himes
authors.affiliation: Genetic Variation and Human Diseases Unit, U946, INSERM, Paris, France.|Institut Universitaire d'Hématologie, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: C
authors.initials: C
authors.lastname: Sarnowski
authors.affiliation: Respiratory Epidemiology, Occupational Medicine and Public Health, National Heart and Lung Institute, Imperial College, London, UK.
authors.forename: C
authors.initials: C
authors.lastname: Minelli
authors.affiliation: Respiratory Epidemiology, Occupational Medicine and Public Health, National Heart and Lung Institute, Imperial College, London, UK.|MRC-PHE Centre for Environment & Health, London, UK.
authors.forename: D
authors.initials: D
authors.lastname: Jarvis
authors.affiliation: Genetic Variation and Human Diseases Unit, U946, INSERM, Paris, France.|Institut Universitaire d'Hématologie, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: E
authors.initials: E
authors.lastname: Bouzigon
authors.affiliation: Merck Research Laboratories, Boston, MA, USA.
authors.forename: D C
authors.initials: DC
authors.lastname: Nickle
authors.affiliation: Institut Universitaire de Cardiologie et de Pneumologie de Québec, Laval University, Québec City, QC, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Laviolette
authors.affiliation: The University of British Columbia James Hogg Research Laboratory, St Paul's Hospital, Vancouver, BC, Canada.|7 Respiratory Division, Department of Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: D
authors.initials: D
authors.lastname: Sin
authors.affiliation: Channing Division of Network Medicine, Department of Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: S T
authors.initials: ST
authors.lastname: Weiss
authors.affiliation: Department of Pulmonary Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.|Groningen Research Institute for Asthma and COPD (GRIAC), University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: van den Berge
authors.affiliation: Groningen Research Institute for Asthma and COPD (GRIAC), University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.|Department of Pediatric Pulmonology and Pediatric Allergology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: G H
authors.initials: GH
authors.lastname: Koppelman
authors.affiliation: Department of Pulmonary Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.|Groningen Research Institute for Asthma and COPD (GRIAC), University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: D S
authors.initials: DS
authors.lastname: Postma
mesh_terms: D000328:Adult; D001249:Asthma / Q000175:diagnosis / Q000235:genetics*; D016535:Bronchial Hyperreactivity / Q000175:diagnosis / Q000235:genetics*; D015331:Cohort Studies; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D012129:Respiratory Function Tests; D012720:Severity of Illness Index; D015534:Trans-Activators; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; C471298:MAML3 protein, human; D008565:Membrane Proteins; D009687:Nuclear Proteins; C112633:PTTG1IP protein, human; D015534:Trans-Activators; D014157:Transcription Factors
keywords: asthma; genetics