Polymorphisms related to ORMDL3 are associated with asthma susceptibility, alterations in transcriptional regulation of ORMDL3, and changes in T_H2 cytokine levels - 06/10/15

Doi : 10.1016/j.jaci.2015.03.014

Michaela Schedel, PhD ^b,^c, Sven Michel, PhD ^a,^c, Vincent D. Gaertner, BSc ^a, Antoaneta A. Toncheva, PhD ^a,^c, Martin Depner, PhD ^d, Aristea Binia, PhD ^a,ⁿ, Maximilian Schieck, PhD ^a,^c, Marie T. Rieger, MD ^d, Norman Klopp, PhD ^e,^f, Andrea von Berg, MD ^g, Albrecht Bufe, MD ^h, Otto Laub, MD ^d, Ernst Rietschel, MD ⁱ, Andrea Heinzmann, MD ^j, Burkard Simma, MD ^k, Christian Vogelberg, MD ^l, Jon Genuneit, MD ^m, Thomas Illig, PhD ^e,^f, Michael Kabesch, MD ^a,^c,^⁎
^a Department of Pediatric Pneumology and Allergy, University Children's Hospital Regensburg (KUNO), Regensburg, Germany
^b Department of Pediatrics, National Jewish Health, Denver, Colo
^c Department of Pediatric Pneumology, Allergy, and Neonatology, Hannover Medical School, Hannover, Germany
^d Children's Hospital, Ludwig-Maximilians-Universität, Munich, Germany
^e Research Group of Molecular Epidemiology, Helmholtz Centre Munich, Neuherberg, Germany
^f Hannover Unified Biobank, Hannover Medical School, Hannover, Germany
^g Research Institute for the Prevention of Allergic Diseases, Children's Department, Marien-Hospital, Wesel, Germany
^h Department of Experimental Pneumology, Ruhr-University, Bochum, Germany
ⁱ University Children's Hospital, University of Cologne, Cologne, Germany
^j University Children's Hospital, Albert Ludwigs University, Freiburg, Germany
^k Children's Department, Feldkirch Hospital, Feldkirch, Austria
^l University Children's Hospital, Technical University Dresden, Germany
^m Institute of Epidemiology and Medical Biometry, Ulm University, Ulm, Germany
ⁿ Nestlé Research Centre, Nutrition & Health Department, Lausanne, Switzerland

^∗Corresponding author: Michael Kabesch, MD, University Children's Hospital Regensburg (KUNO), Department of Pediatric Pneumology and Allergy, Campus St Hedwig, Steinmetzstr 1-3, D-93049 Regensburg, Germany.

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 T_H2 cytokines levels, and therefore might contribute to the childhood asthma susceptibility signal from 17q21.

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Key words : Asthma, association study, polymorphism, ORMDL3, chromosome 17q21, promoter activity, T_H2 cytokine, upstream stimulatory factor, transcriptional regulation

Abbreviations used : Ct, EMSA, EXACT, GWAS, ISAAC II, LD, LpA, MAGICS, OR, ORMDL3, PMA, Ppg, SNP, SP, SPT, USF, UTR

Plan

Methods

Study populations and genetic analyses

Functional analyses of asthma-associated ORMDL3 polymorphisms

Results

SNPs in the 17q21 gene region are associated with asthma phenotypes in a cross-sectional population

SNPs in the proximal ORMDL3 promoter region drive the association between asthma and ORMDL3 haplotypes in a cross-sectional and a case-control population

ORMDL3 SNPs rs8076131 and rs4065275 change transcription factor binding and influence the activity of an ORMDL3 promoter region in an allele-specific manner

Polymorphisms rs8076131 and rs4065275 change gene expression of ORMDL3 and IL-4 and IL-13 cytokine levels in PBMCs after stimulation ex vivo

Discussion

Supported by the German ministry of education and research (BMBF) as part of the national genome research network (NGFN; grant NGFN 01GS 0810) and by the German research foundation (DFG; grant B16 of the SFB 587). Genome-wide association study genotyping was funded by the European Commission as part of the GABRIEL consortium (contract no. 018996 under the Integrated Program LSH-2004-1.2.5-1). M.S. received funding from the European Commission through the Marie Curie International Outgoing Fellowship (IOF; grant 236137).

Disclosure of potential conflict of interest: M. Depner has received research support from the European Research Council. E. Rietschel has board memberships with Vertex, Novartis, MEDA, and Gilead and has received payment for lectures from Vertex and MEDA. M. Kabesch has received research support from the European Union, the German Ministry of Education and Research, and the German Research Foundation and has received payment for lectures from the European Respiratory Society, the European Academy of Allergy and Clinical Immunology, the American Thoracic Society, Novartis, and GlaxoSmithKline. The rest of the authors declare that they have no relevant conflicts of interest.

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Vol 136 - N° 4

P. 893 - octobre 2015 Retour au numéro

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Polymorphisms related to ORMDL3 are associated with asthma susceptibility, alterations in transcriptional regulation of ORMDL3, and changes in T_H2 cytokine levels - 06/10/15

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