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• W1922027044 abstract "Introduction: Asthma affects boys at a 2:1 ratio during childhood while females are affected by asthma twice as often compared to males after puberty.Aims and objectives: This study investigates if and how genetic factors contribute to gender differences in asthma susceptibility.Methods: A GWAS dataset based on the MAGICS/ISAAC II study population (651 cases; 652 controls; 57% males; mean [± SD] age 10.3 ± 2.1 years) was analysed after gender stratification. Additional genotyping for fine mapping of the associated region was performed with MALDI-TOF MS on 7 polymorphisms. Allele-specific effects on protein-DNA interactions were studied with electrophoretic mobility shift assays (EMSA) and changes in promoter activity were investigated with dual-luciferase reporter (DLR) assays.Results: The gender-specific genome wide data analyses identified polymorphisms in the DMRT1 locus to be associated with asthma only in males. Additional fine mapping confirmed that rs3812523 located 1592 base pairs upstream of the first ATG shows strongest association OR=0.55 [95% CI: 0.41-0.74; p=8×10(-5)]. Functional analyses by EMSA revealed allele-specific differences in binding of transcription factors c-Jun and c-Fos to the potential promoter site. DLR assays showed significant, allele-specific differences in promoter activity in HEK293 cells.Conclusions: Using GWAS data we identified genetic variants in DMRT1 to be gender-specific risk factors for asthma development. Allele-specific transcription factor binding and consecutive changes in promoter activity seem to contribute to this effect. The role of DMRT1 in asthma pathogenesis needs to be elucidated further." @default.
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• W1922027044 date "2012-09-01" @default.
• W1922027044 modified "2023-09-22" @default.
• W1922027044 title "A polymorphism in DMRT1 is associated with asthma in boys only and affects promoter activity by allele-specific transcription factor binding" @default.
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