@article {Toncheva3227, author = {Antoaneta Toncheva and Daniel Potaczek and Michaela Schedel and Sven Michel and Natalie Krajnov and Vincent Gaertner and Thomas Illig and Andre Franke and Carla Winkler and Jens Hohlfeld and Christian Vogelberg and Andrea von Berg and Albrecht Bufe and Andrea Heinzmann and Otto Laub and Ernst Rietschel and Burkhard Simma and Jon Genuneit and Michael Kabesch}, title = {Polymorphisms in all three ORMDL genes are associated with asthma and their mRNA expression is increased in asthmatics}, volume = {44}, number = {Suppl 58}, elocation-id = {3227}, year = {2014}, publisher = {European Respiratory Society}, abstract = {Background: The first and well replicated childhood asthma susceptibility locus identified by genome-wide association was 17q21. ORMDL3, located near the top association signal, belongs to the ORMDL gene family including ORMDL1, -2 and -3. ORMDL proteins participate in the sphingolipid metabolism and maintain the ceramide homeostasis.ORMDL3 regulates the intracellular Ca2+ levels, cellular stress responses and lymphocyte activation. Strong sequence homology between ORMDLs and protein conservation among different species suggest that they may have shared functions.Objectives: We hypothesized that single nucleotide polymorphisms (SNPs) in ORMDL genesare associated with asthma and that expression of ORMDLs correlates with asthma.Methods: Associations of 44 genotyped SNPs (Illumina HumanHap300Chip, MALDI-TOF MS) were assessed in 1,303 subjects (651 asthmatics) from MAGIC and ISAAC II studies. Expression in: (1) peripheral blood mononuclear cells (PBMC) (n=55, 8 asthmatics) before and after (48h) allergen stimulation; and (2) blood (n=60, 5 asthmatics) was determined. Allele-specific effects on the ORMDLs expression were evaluated.Results: Sixteen SNPs in all three ORMDL genes were associated with asthma (most in ORMDL3). Baseline expression in PBMC was significantly higher in asthmatics for ORMDL1 (p=1.7*10-6) and -2 (p=4.9*10-5) while induction of ORMDLs upon stimulation was stronger in unaffected subjects. Asthma associated rs8079416 and rs8076131 influenced ORMDL3 expression in allele-specific manner.Conclusions: SNPs in all three ORMDLs are associated with asthma. Asthmatics exhibit increased ORMDL levels, suggesting that ORMDLs contribute to asthma development.These authors contributed equally: Antoaneta Toncheva, Daniel Potaczek and Michaela Schedel.}, issn = {0903-1936}, URL = {https://erj.ersjournals.com/content/44/Suppl_58/3227}, eprint = {https://erj.ersjournals.com/content}, journal = {European Respiratory Journal} }