Schieck, Maximilian ORCID: 0000-0001-5878-0546, Schouten, Jan P., Michel, Sven, Suttner, Kathrin, Toncheva, Antoaneta A., Gaertner, Vincent D., Illig, Thomas, Lipinski, Simone ORCID: 0000-0002-9322-7372, Franke, Andre ORCID: 0000-0003-1530-5811, Klintschar, Michael, Kalayci, Omer, Sahiner, Umit M., Birben, Esra, Melen, Erik, Pershagen, Goeran, Freidin, Maxim B., Ogorodova, Ludmila M., Granell, Raquel ORCID: 0000-0002-4890-4012, Henderson, John, Brunekreef, Bert, Smit, Henriette A., Vogelberg, Christian, von Berg, Andrea, Bufe, Albrecht, Heinzmann, Andrea, Laub, Otto, Rietschel, Ernst, Simma, Burkhard, Genuneit, Jon, Jonigk, Danny, Postma, Dirkje S., Koppelman, Gerard H., Vonk, Judith M., Timens, Wim ORCID: 0000-0002-4146-6363, 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. J. Allergy Clin. Immunol., 138 (2). S. 421 - 432. NEW YORK: MOSBY-ELSEVIER. ISSN 1097-6825

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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: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Schieck, MaximilianUNSPECIFIEDorcid.org/0000-0001-5878-0546UNSPECIFIED
Schouten, Jan P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Michel, SvenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Suttner, KathrinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Toncheva, Antoaneta A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gaertner, Vincent D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Illig, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lipinski, SimoneUNSPECIFIEDorcid.org/0000-0002-9322-7372UNSPECIFIED
Franke, AndreUNSPECIFIEDorcid.org/0000-0003-1530-5811UNSPECIFIED
Klintschar, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kalayci, OmerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sahiner, Umit M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Birben, EsraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Melen, ErikUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pershagen, GoeranUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Freidin, Maxim B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ogorodova, Ludmila M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Granell, RaquelUNSPECIFIEDorcid.org/0000-0002-4890-4012UNSPECIFIED
Henderson, JohnUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brunekreef, BertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Smit, Henriette A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vogelberg, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
von Berg, AndreaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bufe, AlbrechtUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heinzmann, AndreaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Laub, OttoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rietschel, ErnstUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Simma, BurkhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Genuneit, JonUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jonigk, DannyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Postma, Dirkje S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Koppelman, Gerard H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vonk, Judith M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Timens, WimUNSPECIFIEDorcid.org/0000-0002-4146-6363UNSPECIFIED
Boezen, H. MarikeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kabesch, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-268860
DOI: 10.1016/j.jaci.2015.12.1305
Journal or Publication Title: J. Allergy Clin. Immunol.
Volume: 138
Number: 2
Page Range: S. 421 - 432
Date: 2016
Publisher: MOSBY-ELSEVIER
Place of Publication: NEW YORK
ISSN: 1097-6825
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
GENOME; ASSOCIATION; VARIANTS; HEALTH; RISKMultiple languages
Allergy; ImmunologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/26886

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