Schieck, Maximilian and Schouten, Jan P. and Michel, Sven and Suttner, Kathrin and Toncheva, Antoaneta A. and Gaertner, Vincent D. and Illig, Thomas and Lipinski, Simone and Franke, Andre and Klintschar, Michael and Kalayci, Omer and Sahiner, Umit M. and Birben, Esra and Melen, Erik and Pershagen, Goeran and Freidin, Maxim B. and Ogorodova, Ludmila M. and Granell, Raquel and Henderson, John and Brunekreef, Bert and Smit, Henriette A. and Vogelberg, Christian and von Berg, Andrea and Bufe, Albrecht and Heinzmann, Andrea and Laub, Otto and Rietschel, Ernst and Simma, Burkhard and Genuneit, Jon and Jonigk, Danny and Postma, Dirkje S. and Koppelman, Gerard H. and Vonk, Judith M. and Timens, Wim and Boezen, H. Marike and Kabesch, Michael (2016) 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. JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, 138 (2). pp. 421-431. ISSN 0091-6749, 1097-6825
Full text not available from this repository. (Request a copy)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 predispositionto 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 x 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | HUMAN GENOME; ASSOCIATION; VARIANTS; HEALTH; COHORT; RISK; Asthma; genetic association; DMRT1; interaction; rs3812523; sex; single nucleotide polymorphism |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Kinder- und Jugendmedizin |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 03 Apr 2019 09:20 |
| Last Modified: | 03 Apr 2019 09:20 |
| URI: | https://pred.uni-regensburg.de/id/eprint/3553 |
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