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Childhood asthma is associated with mutations and gene expression differences of ORMDL genes that can interact

: Toncheva, A.A.; Potaczek, D.P.; Schedel, M.; Gersting, S.W.; Michel, S.; Krajnov, N.; Gaertner, V.D.; Klingbeil, J.M.; Illig, T.; Franke, A.; Winkler, Carla; Hohlfeld, Jens M.; Vogelberg, C.; Berg, A. von; Bufe, A.; Heinzmann, A.; Laub, O.; Rietschel, E.; Simma, B.; Genuneit, J.; Muntau, A.C.; Kabesch, Michael


Allergy. European journal of allergy and clinical immunology 70 (2015), No.10, pp.1288-1299
ISSN: 0105-4538
ISSN: 1398-9995
Journal Article
Fraunhofer ITEM ()
bioluminescence energy transfer; cildhood asthma; peripheral blood mononuclear cells; protein-protein interaction; single nucleotide polymorphism

BACKGROUND: Genome-wide association studies identified ORMDL3 as a plausible asthma candidate gene. ORMDL proteins regulate sphingolipid metabolism and ceramide homeostasis, participate in lymphocyte activation and eosinophil recruitment. Strong sequence homology between the three ORMDL genes and ORMDL protein conservation amongst different species suggest that they may have shared functions. We hypothesized that if single nucleotide polymorphisms (SNPs) in ORMDL3 alter its gene expression and play a role in asthma, variants in ORMDL1 and ORMDL2 might also be associated with asthma.
METHODS: Asthma associations of 44 genotyped SNPs were determined in at least 1,303 subjects (651 asthmatics). ORMDLs expression was evaluated in peripheral blood mononuclear cells (PBMC) from 55 subjects (8 asthmatics) before and after allergen stimulation, and in blood (n=60, 5 asthmatics). Allele-specific cis-effects on ORMDLs expression were assessed. Interactions between human ORMDL proteins were determined in living cells.
RESULTS: Sixteen SNPs in all three ORMDLs were associated with asthma (14 in ORMDL3). Baseline expression of ORMDL1 (p=1.7*10-6) and ORMDL2 (p=4.9*10-5) was significantly higher in PBMC from asthmatics, while induction of ORMDLs upon stimulation was stronger in non-asthmatics. Disease-associated alleles (rs8079416, rs4795405, rs3902920) alter ORMDL3 expression. ORMDL proteins formed homo- and heterooligomers and displayed similar patterns of interaction with SERCA2 and SPT1.
CONCLUSIONS: Polymorphisms in ORMDL genes are associated with asthma. Asthmatics exhibit increased ORMDL levels, suggesting that ORMDLs contribute to asthma. Formation of heterooligomers and similar interaction patterns with proteins involved in calcium homeostasis and sphingolipid metabolism could indicate shared biological roles of ORMDLs, influencing airway remodeling and hyperresponsiveness.