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. 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.
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.
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.
Authors: Giuliana Ferrante; Salvatore Fasola; Giovanna Cilluffo; Giorgio Piacentini; Giovanni Viegi; Stefania La Grutta Journal: Front Public Health Date: 2022-06-14
Authors: Odunayo I Azeez; Jan G Myburgh; Ana-Mari Bosman; Jonathan Featherston; Kgomotso P Sibeko-Matjilla; Marinda C Oosthuizen; Joseph P Chamunorwa Journal: PLoS One Date: 2019-11-18 Impact factor: 3.240