TY - JOUR T1 - Polymorphisms in all three<em> ORMDL</em> genes are associated with asthma and their mRNA expression is increased in asthmatics JF - European Respiratory Journal JO - Eur Respir J VL - 44 IS - Suppl 58 SP - 3227 AU - Antoaneta Toncheva AU - Daniel Potaczek AU - Michaela Schedel AU - Sven Michel AU - Natalie Krajnov AU - Vincent Gaertner AU - Thomas Illig AU - Andre Franke AU - Carla Winkler AU - Jens Hohlfeld AU - Christian Vogelberg AU - Andrea von Berg AU - Albrecht Bufe AU - Andrea Heinzmann AU - Otto Laub AU - Ernst Rietschel AU - Burkhard Simma AU - Jon Genuneit AU - Michael Kabesch Y1 - 2014/09/01 UR - http://erj.ersjournals.com/content/44/Suppl_58/3227.abstract N2 - 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. ER -