title: Doublesex and mab-3 related transcription factor 1 (DMRT1) is a sex-specific genetic determinant of childhood-onset asthma and is expressed in testis and macrophages.
abstract: Asthma is a disease affecting more boys than girls in childhood and more women than men in adulthood. The mechanisms behind these sex-specific differences are not yet understood.
  
  
  
  We analyzed whether and how genetic factors contribute to sex-specific predisposition to childhood-onset asthma.
  
  
  
  Interactions between sex and polymorphisms on childhood asthma risk were evaluated in the Multicentre Asthma Genetics in Childhood Study (MAGICS)/Phase II International Study of Asthma and Allergies in Childhood (ISAAC II) population on a genome-wide level, and findings were validated in independent populations. Genetic fine mapping of sex-specific asthma association signals was performed, and putatively causal polymorphisms were characterized in vitro by using electrophoretic mobility shift and luciferase activity assays. Gene and protein expression of the identified gene doublesex and mab-3 related transcription factor 1 (DMRT1) were measured in different human tissues by using quantitative real-time PCR and immunohistochemistry.
  
  
  
  Polymorphisms in the testis-associated gene DMRT1 displayed interactions with sex on asthma status in a population of primarily clinically defined asthmatic children and nonasthmatic control subjects (lowest P = 5.21 × 10(-6)). Replication of this interaction was successful in 2 childhood populations clinically assessed for asthma but showed heterogeneous results in other population-based samples. Polymorphism rs3812523 located in the putative DMRT1 promoter was associated with allele-specific changes in transcription factor binding and promoter activity in vitro. DMRT1 expression was observed not only in the testis but also in lung macrophages.
  
  
  
  DMRT1 might influence sex-specific patterns of childhood asthma, and its expression in testis tissue and lung macrophages suggests a potential involvement in hormone or immune cell regulation.
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: Maximilian
authors.initials: M
authors.lastname: Schieck
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Epidemiology, Groningen, The Netherlands.
authors.forename: Jan P
authors.initials: JP
authors.lastname: Schouten
authors.affiliation: Department of Pediatric Pneumology and Allergy, University Children's Hospital Regensburg (KUNO), Regensburg, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Michel
authors.affiliation: ZAUM-Center of Allergy and Environment, Technische Universität München and Helmholtz Center Munich, Munich, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Suttner
authors.affiliation: Department of Pediatric Pneumology and Allergy, University Children's Hospital Regensburg (KUNO), Regensburg, Germany.
authors.forename: Antoaneta A
authors.initials: AA
authors.lastname: Toncheva
authors.affiliation: Department of Pediatric Pneumology and Allergy, University Children's Hospital Regensburg (KUNO), Regensburg, Germany.
authors.forename: Vincent D
authors.initials: VD
authors.lastname: Gaertner
authors.affiliation: Hannover Unified Biobank, Hannover Medical School, Hannover, Germany; Research Unit of Molecular Epidemiology, Helmholtz Center Munich, Neuherberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Illig
authors.affiliation: Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Lipinski
authors.affiliation: Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany.
authors.forename: Andre
authors.initials: A
authors.lastname: Franke
authors.affiliation: Institute for Legal Medicine, Hannover Medical School, Hannover, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Klintschar
authors.affiliation: Pediatric Allergy and Asthma Unit, Department of Pediatrics, Hacettepe University, Ankara, Turkey.
authors.forename: Omer
authors.initials: O
authors.lastname: Kalayci
authors.affiliation: Pediatric Allergy and Asthma Unit, Department of Pediatrics, Hacettepe University, Ankara, Turkey.
authors.forename: Umit M
authors.initials: UM
authors.lastname: Sahiner
authors.affiliation: Pediatric Allergy and Asthma Unit, Department of Pediatrics, Hacettepe University, Ankara, Turkey.
authors.forename: Esra
authors.initials: E
authors.lastname: Birben
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; Sachs' Children and Youth Hospital, Stockholm, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Melén
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Göran
authors.initials: G
authors.lastname: Pershagen
authors.affiliation: Research Institute for Medical Genetics, Tomsk, Russia.
authors.forename: Maxim B
authors.initials: MB
authors.lastname: Freidin
authors.affiliation: Siberian State Medical University, Tomsk, Russia.
authors.forename: Ludmila M
authors.initials: LM
authors.lastname: Ogorodova
authors.affiliation: School of Social and Community Medicine, Faculty of Medicine and Dentistry, University of Bristol, Bristol, United Kingdom.
authors.forename: Raquel
authors.initials: R
authors.lastname: Granell
authors.affiliation: School of Social and Community Medicine, Faculty of Medicine and Dentistry, University of Bristol, Bristol, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Henderson
authors.affiliation: Institute for Risk Assessment Sciences, University of Utrecht, Utrecht, The Netherlands; Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Bert
authors.initials: B
authors.lastname: Brunekreef
authors.affiliation: Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Henriëtte A
authors.initials: HA
authors.lastname: Smit
authors.affiliation: University Children's Hospital, Technical University Dresden, Dresden, Germany.
authors.forename: Christian
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: Andrea
authors.initials: A
authors.lastname: von Berg
authors.affiliation: Department of Experimental Pneumology, Ruhr University, Bochum, Germany.
authors.forename: Albrecht
authors.initials: A
authors.lastname: Bufe
authors.affiliation: University Children's Hospital, Albert Ludwigs University, Freiburg, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Heinzmann
authors.affiliation: Kinder- und Jugendarztpraxis Laub, Rosenheim, Germany.
authors.forename: Otto
authors.initials: O
authors.lastname: Laub
authors.affiliation: University Children's Hospital, University of Cologne, Cologne, Germany.
authors.forename: Ernst
authors.initials: E
authors.lastname: Rietschel
authors.affiliation: Children's Department, University Teaching Hospital, Landeskrankenhaus Feldkirch, Feldkirch, Austria.
authors.forename: Burkhard
authors.initials: B
authors.lastname: Simma
authors.affiliation: Institute of Epidemiology and Medical Biometry, Ulm University, Ulm, Germany.
authors.forename: Jon
authors.initials: J
authors.lastname: Genuneit
authors.affiliation: Institute of Pathology, Hannover Medical School, Hannover, Germany.
authors.forename: Danny
authors.initials: D
authors.lastname: Jonigk
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Pulmonology, GRIAC Research Institute, Groningen, The Netherlands.
authors.forename: Dirkje S
authors.initials: DS
authors.lastname: Postma
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Pediatric Pulmonology and Pediatric Allergology, Beatrix Children's Hospital, GRIAC Research Institute, Groningen, The Netherlands.
authors.forename: Gerard H
authors.initials: GH
authors.lastname: Koppelman
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Epidemiology, Groningen, The Netherlands.
authors.forename: Judith M
authors.initials: JM
authors.lastname: Vonk
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Groningen, The Netherlands.
authors.forename: Wim
authors.initials: W
authors.lastname: Timens
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Epidemiology, Groningen, The Netherlands.
authors.forename: H Marike
authors.initials: HM
authors.lastname: Boezen
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. Electronic address: michael.kabesch@ukr.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Kabesch
mesh_terms: D017668:Age of Onset; D000483:Alleles; D001249:Asthma / Q000235:genetics* / Q000276:immunology; D001665:Binding Sites; D002648:Child; D002874:Chromosome Mapping; D005260:Female; D015870:Gene Expression; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D007150:Immunohistochemistry; D015810:Linkage Disequilibrium; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D008297:Male; D016017:Odds Ratio; D009928:Organ Specificity / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012737:Sex Factors; D013737:Testis / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: C110547:DMRT1 protein; D014157:Transcription Factors
keywords: Asthma; DMRT1; genetic association; interaction; rs3812523; sex; single nucleotide polymorphism