RT Journal Article SR Electronic T1 Genetic variation in human RHS7 of the TH2 locus control region influences DNA methylation and is associated with IgE JF European Respiratory Journal JO Eur Respir J FD European Respiratory Society SP 3229 VO 44 IS Suppl 58 A1 Maximilian Schieck A1 Vishwas Sharma A1 Sven Michel A1 Antoaneta A. Toncheva A1 Daniel P. Potaczek A1 Luise Worth A1 Jon Genuneit A1 Anja Kretschmer A1 Martin Depner A1 Jean-Charles Dalphin A1 Josef Riedler A1 Remo Frei A1 Juha Pekkanen A1 Jörg Tost A1 Michael Kabesch YR 2014 UL http://erj.ersjournals.com/content/44/Suppl_58/3229.abstract AB Background: Previously, polymorphisms in the TH2 cytokine locus on chromosome 5q31 showed associations with asthma and IgE (Li X. et al. J Allergy Clin Immunol 2010; 125(2):328-335e11). While the locus contains interleukins (IL) 4, 5 and 13 essential for TH2 differentiation the strongest association signal mapped to the RAD50 gene. In mice, Rad50 harbors an epigenetic locus control region defined by four Rad50 DNase I hypersensitive sites (RHS4-7) of which RHS7 undergoes the strongest regulatory changes during TH2 differentiation (Lee G.R. et al. Nat Immunol 2005; 6(1):42-48). We investigated if the human homolog of RHS7 influences TH2 locus gene expression or DNA methylation and if associations with asthma or IgE exist.Methods: Human RHS7 was fine mapped for polymorphisms based on 1000 Genomes data. Allele-specific changes in transcription factor binding were analyzed with electrophoretic mobility shift assays. Effects on mRNA expression (RAD50, IL4, IL13) were measured in whole blood (n=100 adults). Differences in DNA methylation were studied in cord blood (n=73) and at age 4.5 years (n=61) in the PASTURE cohort. Genetic association with childhood asthma or total serum IgE was tested in the MAGICS/ISAAC II population (n=1,145).Results: Fine mapping identified the polymorphism rs2240032 to be located in RHS7. Allele-specific transcription factor binding was observed in EMSA. Furthermore, significant polymorphism effects were present on methylation in the IL13 promoter region (cord blood: p=0.003; age 4.5 years: p=0.032) and on IgE levels (p=0.023).Conclusion: Polymorphism rs2240032 in the TH2 cytokine locus influences 5q31 DNA methylation and total IgE levels.