Universität zu Köln

Schedel, Michaela ORCID: 0000-0001-8465-2986, Michel, Sven, Gaertner, Vincent D., Toncheva, Antoaneta A., Depner, Martin, Binia, Aristea ORCID: 0000-0002-8327-049X, Schieck, Maximilian ORCID: 0000-0001-5878-0546, Rieger, Marie T., Klopp, Norman, von Berg, Andrea, Bufe, Albrecht ORCID: 0000-0001-7335-9362, Laub, Otto, Rietschel, Ernst, Heinzmann, Andrea, Simma, Burkard, Vogelberg, Christian, Genuneit, Jon, Illig, Thomas and Kabesch, Michael (2015). Polymorphisms related to ORMDL3 are associated with asthma susceptibility, alterations in transcriptional regulation of ORMDL3, and changes in T(H)2 cytokine levels. J. Allergy Clin. Immunol., 136 (4). S. 893 - 918. NEW YORK: MOSBY-ELSEVIER. ISSN 1097-6825

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Abstract

Background: Chromosome 17q21, harboring the orosomucoid 1-like 3 (ORMDL3) gene, has been consistently associated with childhood asthma in genome-wide association studies. Objective: We investigated genetic variants in and around ORMDL3 that can change the function of ORMDL3 and thus contribute to asthma susceptibility. Methods: We performed haplotype analyses and fine mapping of the ORMDL3 locus in a cross-sectional (International Study of Asthma and Allergies in Childhood Phase II, n = 3557 total subjects, n = 281 asthmatic patients) and case-control (Multicenter Asthma Genetics in Childhood Study/International Study of Asthma and Allergies in Childhood Phase II, n = 1446 total subjects, n = 763 asthmatic patients) data set to identify putative causal single nucleotide polymorphisms (SNPs) in the locus. Top asthma-associated polymorphisms were analyzed for allele-specific effects on transcription factor binding and promoter activity in vitro and gene expression in PBMCs after stimulation ex vivo. Results: Two haplotypes (H1 and H2) were significantly associated with asthma in the cross-sectional (P = 9.9 x 10(-5) and P = .0035, respectively) and case-control (P = 3.15 x 10(-8) and P = .0021, respectively) populations. Polymorphisms rs8076131 and rs4065275 were identified to drive these effects. For rs4065275, a quantitative difference in transcription factor binding was found, whereas for rs8076131, changes in upstream stimulatory factor 1 and 2 transcription factor binding were observed in vitro by using different cell lines and PBMCs. This might contribute to detected alterations in luciferase activity paralleled with changes in ORMDL3 gene expression and IL-4 and IL-13 cytokine levels ex vivo in response to innate and adaptive stimuli in an allele-specific manner. Both SNPs were in strong linkage disequilibrium with asthma-associated 17q21 SNPs previously related to altered ORMDL3 gene expression. Conclusion: Polymorphisms in a putative promoter region of ORMDL3, which are associated with childhood asthma, alter transcriptional regulation of ORMDL3, correlate with changes in T(H)2 cytokines levels, and therefore might contribute to the childhood asthma susceptibility signal from 17q21.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Schedel, Michaela UNSPECIFIED orcid.org/0000-0001-8465-2986 UNSPECIFIED Michel, Sven UNSPECIFIED UNSPECIFIED UNSPECIFIED Gaertner, Vincent D. UNSPECIFIED UNSPECIFIED UNSPECIFIED Toncheva, Antoaneta A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Depner, Martin UNSPECIFIED UNSPECIFIED UNSPECIFIED Binia, Aristea UNSPECIFIED orcid.org/0000-0002-8327-049X UNSPECIFIED Schieck, Maximilian UNSPECIFIED orcid.org/0000-0001-5878-0546 UNSPECIFIED Rieger, Marie T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Klopp, Norman UNSPECIFIED UNSPECIFIED UNSPECIFIED von Berg, Andrea UNSPECIFIED UNSPECIFIED UNSPECIFIED Bufe, Albrecht UNSPECIFIED orcid.org/0000-0001-7335-9362 UNSPECIFIED Laub, Otto UNSPECIFIED UNSPECIFIED UNSPECIFIED Rietschel, Ernst UNSPECIFIED UNSPECIFIED UNSPECIFIED Heinzmann, Andrea UNSPECIFIED UNSPECIFIED UNSPECIFIED Simma, Burkard UNSPECIFIED UNSPECIFIED UNSPECIFIED Vogelberg, Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED Genuneit, Jon UNSPECIFIED UNSPECIFIED UNSPECIFIED Illig, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Kabesch, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-392080
DOI:	10.1016/j.jaci.2015.03.014
Journal or Publication Title:	J. Allergy Clin. Immunol.
Volume:	136
Number:	4
Page Range:	S. 893 - 918
Date:	2015
Publisher:	MOSBY-ELSEVIER
Place of Publication:	NEW YORK
ISSN:	1097-6825
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language ENDOPLASMIC-RETICULUM STRESS; SIGNAL TRANSDUCER; EXPRESSION; GENE; ACTIVATION; CHILDHOOD; PROMOTER; CHILDREN; VARIANTS; CELLS Multiple languages Allergy; Immunology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/39208