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J Allergy Clin Immunol. 2015 Oct;136(4):893-903.e14. doi: 10.1016/j.jaci.2015.03.014. Epub 2015 Apr 28.

Polymorphisms related to ORMDL3 are associated with asthma susceptibility, alterations in transcriptional regulation of ORMDL3, and changes in TH2 cytokine levels.

Author information

1
Department of Pediatrics, National Jewish Health, Denver, Colo; Department of Pediatric Pneumology, Allergy, and Neonatology, Hannover Medical School, Hannover, Germany.
2
Department of Pediatric Pneumology and Allergy, University Children's Hospital Regensburg (KUNO), Regensburg, Germany; Department of Pediatric Pneumology, Allergy, and Neonatology, Hannover Medical School, Hannover, Germany.
3
Department of Pediatric Pneumology and Allergy, University Children's Hospital Regensburg (KUNO), Regensburg, Germany.
4
Children's Hospital, Ludwig-Maximilians-Universität, Munich, Germany.
5
Department of Pediatric Pneumology and Allergy, University Children's Hospital Regensburg (KUNO), Regensburg, Germany; Nestlé Research Centre, Nutrition & Health Department, Lausanne, Switzerland.
6
Research Group of Molecular Epidemiology, Helmholtz Centre Munich, Neuherberg, Germany; Hannover Unified Biobank, Hannover Medical School, Hannover, Germany.
7
Research Institute for the Prevention of Allergic Diseases, Children's Department, Marien-Hospital, Wesel, Germany.
8
Department of Experimental Pneumology, Ruhr-University, Bochum, Germany.
9
University Children's Hospital, University of Cologne, Cologne, Germany.
10
University Children's Hospital, Albert Ludwigs University, Freiburg, Germany.
11
Children's Department, Feldkirch Hospital, Feldkirch, Austria.
12
University Children's Hospital, Technical University Dresden, Germany.
13
Institute of Epidemiology and Medical Biometry, Ulm University, Ulm, Germany.
14
Department of Pediatric Pneumology and Allergy, University Children's Hospital Regensburg (KUNO), Regensburg, Germany; Department of Pediatric Pneumology, Allergy, and Neonatology, Hannover Medical School, Hannover, Germany. Electronic address: michael.kabesch@ukr.de.

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 × 10(-5) and P = .0035, respectively) and case-control (P = 3.15 × 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 TH2 cytokines levels, and therefore might contribute to the childhood asthma susceptibility signal from 17q21.

KEYWORDS:

Asthma; ORMDL3; T(H)2 cytokine; association study; chromosome 17q21; polymorphism; promoter activity; transcriptional regulation; upstream stimulatory factor

PMID:
25930191
DOI:
10.1016/j.jaci.2015.03.014
[Indexed for MEDLINE]

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