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

• DOI: 10.1016/j.jaci.2015.12.1305
• Publication Date: 2016-02-20T20:36:29Z
• Authors: Maximilian Schieck; Jan P. Schouten; Sven Michel; Kathrin Suttner; Antoaneta A. Tonc...; 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
• Keywords: Male; genetic association; 610; interaction; Gene Expression; VARIANTS; DMRT1; Polymorphism, Single Nucleotide; Linkage Disequilibrium; 03 medical and health sciences; SDG 3 - Good Health and Well-being; single nucleotide polymorphism; Taverne; Journal Article; Odds Ratio; sex; HUMAN GENOME; Humans; COHORT; Genetic Predisposition to Disease; Age of Onset; Child; Promoter Regions, Genetic; Alleles; RISK; 0303 health sciences; Asthma ; Dmrt1 ; Genetic Association ; Interaction ; Rs3812523 ; Sex ; Single Nucleotide Polymorphism; Binding Sites; Macrophages; Chromosome Mapping; ASSOCIATION; rs3812523; Immunohistochemistry; Asthma; 3. Good health; Genetic Loci; Organ Specificity; Female; HEALTH; Genome-Wide Association Study

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