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

Maximilian Schieck; Jan P Schouten; Sven Michel; Kathrin Suttner; Antoaneta A Toncheva; Vincent D Gaertner; Thomas Illig; Simone Lipinski; Andre Franke; Michael Klintschar; Omer Kalayci; Umit M Sahiner; Esra Birben; Erik Melén; Göran Pershagen; Maxim B Freidin; Ludmila M Ogorodova; Raquel Granell; John Henderson; Bert Brunekreef; Henriëtte A Smit; Christian Vogelberg; Andrea von Berg; Albrecht Bufe; Andrea Heinzmann; Otto Laub; Ernst Rietschel; Burkhard Simma; Jon Genuneit; Danny Jonigk; Dirkje S Postma; Gerard H Koppelman; Judith M Vonk; Wim Timens; H Marike Boezen; Michael Kabesch

doi:10.1016/j.jaci.2015.12.1305

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

J Allergy Clin Immunol. 2016 Aug;138(2):421-31. doi: 10.1016/j.jaci.2015.12.1305. Epub 2016 Feb 20.

Authors

Maximilian Schieck¹, Jan P Schouten², Sven Michel³, Kathrin Suttner⁴, Antoaneta A Toncheva³, Vincent D Gaertner³, Thomas Illig⁵, Simone Lipinski⁶, Andre Franke⁶, Michael Klintschar⁷, Omer Kalayci⁸, Umit M Sahiner⁸, Esra Birben⁸, Erik Melén⁹, Göran Pershagen¹⁰, Maxim B Freidin¹¹, Ludmila M Ogorodova¹², Raquel Granell¹³, John Henderson¹³, Bert Brunekreef¹⁴, Henriëtte A Smit¹⁵, Christian Vogelberg¹⁶, Andrea von Berg¹⁷, Albrecht Bufe¹⁸, Andrea Heinzmann¹⁹, Otto Laub²⁰, Ernst Rietschel²¹, Burkhard Simma²², Jon Genuneit²³, Danny Jonigk²⁴, Dirkje S Postma²⁵, Gerard H Koppelman²⁶, Judith M Vonk², Wim Timens²⁷, H Marike Boezen², Michael Kabesch²⁸

Affiliations

¹ 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.
² University of Groningen, University Medical Center Groningen, Department of Epidemiology, Groningen, The Netherlands.
³ Department of Pediatric Pneumology and Allergy, University Children's Hospital Regensburg (KUNO), Regensburg, Germany.
⁴ ZAUM-Center of Allergy and Environment, Technische Universität München and Helmholtz Center Munich, Munich, Germany.
⁵ Hannover Unified Biobank, Hannover Medical School, Hannover, Germany; Research Unit of Molecular Epidemiology, Helmholtz Center Munich, Neuherberg, Germany.
⁶ Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany.
⁷ Institute for Legal Medicine, Hannover Medical School, Hannover, Germany.
⁸ Pediatric Allergy and Asthma Unit, Department of Pediatrics, Hacettepe University, Ankara, Turkey.
⁹ Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; Sachs' Children and Youth Hospital, Stockholm, Sweden.
¹⁰ Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
¹¹ Research Institute for Medical Genetics, Tomsk, Russia.
¹² Siberian State Medical University, Tomsk, Russia.
¹³ School of Social and Community Medicine, Faculty of Medicine and Dentistry, University of Bristol, Bristol, United Kingdom.
¹⁴ 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.
¹⁵ Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.
¹⁶ University Children's Hospital, Technical University Dresden, Dresden, Germany.
¹⁷ Research Institute for the Prevention of Allergic Diseases, Children's Department, Marien-Hospital, Wesel, Germany.
¹⁸ Department of Experimental Pneumology, Ruhr University, Bochum, Germany.
¹⁹ University Children's Hospital, Albert Ludwigs University, Freiburg, Germany.
²⁰ Kinder- und Jugendarztpraxis Laub, Rosenheim, Germany.
²¹ University Children's Hospital, University of Cologne, Cologne, Germany.
²² Children's Department, University Teaching Hospital, Landeskrankenhaus Feldkirch, Feldkirch, Austria.
²³ Institute of Epidemiology and Medical Biometry, Ulm University, Ulm, Germany.
²⁴ Institute of Pathology, Hannover Medical School, Hannover, Germany.
²⁵ University of Groningen, University Medical Center Groningen, Department of Pulmonology, GRIAC Research Institute, Groningen, The Netherlands.
²⁶ University of Groningen, University Medical Center Groningen, Department of Pediatric Pulmonology and Pediatric Allergology, Beatrix Children's Hospital, GRIAC Research Institute, Groningen, The Netherlands.
²⁷ University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, Groningen, The Netherlands.
²⁸ 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.

PMID: 26906082
DOI: 10.1016/j.jaci.2015.12.1305

Abstract

Background: 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.

Objective: We analyzed whether and how genetic factors contribute to sex-specific predisposition to childhood-onset asthma.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords: Asthma; DMRT1; genetic association; interaction; rs3812523; sex; single nucleotide polymorphism.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Age of Onset
Alleles
Asthma / genetics*
Asthma / immunology
Binding Sites
Child
Chromosome Mapping
Female
Gene Expression*
Genetic Loci
Genetic Predisposition to Disease*
Genome-Wide Association Study
Humans
Immunohistochemistry
Linkage Disequilibrium
Macrophages / immunology
Macrophages / metabolism*
Male
Odds Ratio
Organ Specificity / genetics
Polymorphism, Single Nucleotide
Promoter Regions, Genetic
Sex Factors
Testis / metabolism*
Transcription Factors / genetics*
Transcription Factors / metabolism

Substances

DMRT1 protein
Transcription Factors

Abstract

Publication types

MeSH terms

Substances

Grants and funding