Universität zu Köln

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, C., Hohlfeld, J. M., Vogelberg, C., von Berg, A., Bufe, A., Heinzmann, A., Laub, O., Rietschel, E., Simma, B., Genuneit, J., Muntau, A. C. and Kabesch, M. (2015). Childhood asthma is associated with mutations and gene expression differences of ORMDL genes that can interact. Allergy, 70 (10). S. 1288 - 1300. HOBOKEN: WILEY. ISSN 1398-9995

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Abstract

Background: Genomewide association studies identified ORMDL3 as a plausible asthma candidate gene. ORMDL proteins regulate sphingolipid metabolism and ceramide homeostasis and participate in lymphocyte activation and eosinophil recruitment. Strong sequence homology between the three ORMDL genes and ORMDL protein conservation among 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 1303 subjects (651 asthmatics). ORMDL expression was evaluated in peripheral blood mononuclear cells (PBMC) from 55 subjects (eight asthmatics) before and after allergen stimulation, and in blood (n = 60, 5 asthmatics). Allele-specific cis-effects on ORMDL 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 x 10(-6)) and ORMDL2 (P = 4.9 x 10(-5)) was significantly higher in PBMC from asthmatics, while induction of ORMDLs upon stimulation was stronger in nonasthmatics. 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Toncheva, A. A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Potaczek, D. P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schedel, M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Gersting, S. W. UNSPECIFIED UNSPECIFIED UNSPECIFIED Michel, S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Krajnov, N. UNSPECIFIED UNSPECIFIED UNSPECIFIED Gaertner, V. D. UNSPECIFIED UNSPECIFIED UNSPECIFIED Klingbeil, J. M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Illig, T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Franke, A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Winkler, C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hohlfeld, J. M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Vogelberg, C. UNSPECIFIED UNSPECIFIED UNSPECIFIED von Berg, A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Bufe, A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Heinzmann, A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Laub, O. UNSPECIFIED UNSPECIFIED UNSPECIFIED Rietschel, E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Simma, B. UNSPECIFIED UNSPECIFIED UNSPECIFIED Genuneit, J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Muntau, A. C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kabesch, M. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-391327
DOI:	10.1111/all.12652
Journal or Publication Title:	Allergy
Volume:	70
Number:	10
Page Range:	S. 1288 - 1300
Date:	2015
Publisher:	WILEY
Place of Publication:	HOBOKEN
ISSN:	1398-9995
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language PROTEIN-PROTEIN INTERACTION; RESONANCE ENERGY-TRANSFER; POLYMORPHISMS; BASOPHILS; VARIANTS; INSIGHTS; MEDIATE; CELL; TOOL Multiple languages Allergy; Immunology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/39132