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

Publication date: Available online 20 February 2016
Source:Journal of Allergy and Clinical Immunology
Author(s): 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
BackgroundAsthma 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.ObjectiveWe analyzed whether and how genetic factors contribute to sex-specific predisposition to childhood-onset asthma.MethodsInteractions 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.ResultsPolymorphisms 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.ConclusionDMRT1 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.



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