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Epigenome-wide meta-analysis of DNA methylation and childhood asthma

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Reese, SE and Xu, C-J and den Dekker, HT and Lee, MK and Sikdar, S and Ruiz-Arenas, C and Merid, SK and Rezwan, FI and Page, CM and Ullemar, V and Melton, PE and Oh, SS and Yang, IV and Burrows, K and Soderhall, C and Jima, DD and Gao, L and Arathimos, R and Kupers, LK and Wielscher, M and Rzehak, P and Lahti, J and Laprise, C and Madore, A-M and Ward, J and Bennett, BD and Wang, T and Bell, DA and Vonk, JM and Haberg, SE and Zhao, S and Karlsson, R and Hollams, E and Hu, D and Richards, AJ and Bergstrom, A and Sharp, GC and Felix, JF and Bustamante, M and Gruzieva, O and Maguire, RL and Gilliland, F and Baiz, N and Nohr, EA and Corpeleijn, E and Sebert, S and Karmaus, W and Grote, V and Kajantie, E and Magnus, MC and Ortqvist, AK and Eng, C and Liu, AH and Kull, I and Jaddoe, VWV and Sunyer, J and Kere, J and Hoyo, C and Annesi-Maesano, I and Arshad, SH and Koletzko, B and Brunekreef, B and Binder, EB and Raikkonen, K and Reischl, E and Holloway, JW and Jarvelin, M-R and Snieder, H and Kazmi, N and Breton, CV and Murphy, SK and Pershagen, G and Anto, JM and Relton, CL and Schwartz, DA and Burchard, EG and Huang, R-C and Nystad, W and Almqvist, C and Henderson, AJ and Melen, E and Duijts, L and Koppelman, GH and London, SJ and the BIOS consortium, Epigenome-wide meta-analysis of DNA methylation and childhood asthma, Journal of Allergy and Clinical Immunology, 143, (6) pp. 2062-2074. ISSN 0091-6749 (2019) [Refereed Article]


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Copyright Statement

Copyright 2021 Elsevier B.V. Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology. This is an open access article under the CC BY license (http://creative commons.org/licenses/by/4.0/).

DOI: doi:10.1016/j.jaci.2018.11.043

Abstract

Background: Epigenetic mechanisms, including methylation, can contribute to childhood asthma. Identifying DNA methylation profiles in asthmatic patients can inform disease pathogenesis.

Objective: We sought to identify differential DNA methylation in newborns and children related to childhood asthma.

Methods: Within the Pregnancy And Childhood Epigenetics consortium, we performed epigenome-wide meta-analyses of school-age asthma in relation to CpG methylation (Illumina450K) in blood measured either in newborns, in prospective analyses, or cross-sectionally in school-aged children. We also identified differentially methylated regions.

Results: In newborns (8 cohorts, 668 cases), 9 CpGs (and 35 regions) were differentially methylated (epigenome-wide significance, false discovery rate < 0.05) in relation to asthma development. In a cross-sectional meta-analysis of asthma and methylation in children (9 cohorts, 631 cases), we identified 179 CpGs (false discovery rate < 0.05) and 36 differentially methylated regions. In replication studies of methylation in other tissues, most of the 179 CpGs discovered in blood replicated, despite smaller sample sizes, in studies of nasal respiratory epithelium or eosinophils. Pathway analyses highlighted enrichment for asthma-relevant immune processes and overlap in pathways enriched both in newborns and children. Gene expression correlated with methylation at most loci. Functional annotation supports a regulatory effect on gene expression at many asthma-associated CpGs. Several implicated genes are targets for approved or experimental drugs, including IL5RA and KCNH2.

Conclusion: Novel loci differentially methylated in newborns represent potential biomarkers of risk of asthma by school age. Cross-sectional associations in children can reflect both risk for and effects of disease. Asthma-related differential methylation in blood in children was substantially replicated in eosinophils and respiratory epithelium.

Item Details

Item Type:Refereed Article
Keywords:epigenetics, asthma, childhood, drug development, methylation, newborn
Research Division:Biological Sciences
Research Group:Genetics
Research Field:Epigenetics (incl. genome methylation and epigenomics)
Objective Division:Health
Objective Group:Clinical health
Objective Field:Clinical health not elsewhere classified
UTAS Author:Melton, PE (Dr Phillip Melton)
ID Code:144385
Year Published:2019
Web of Science® Times Cited:66
Deposited By:Menzies Institute for Medical Research
Deposited On:2021-05-19
Last Modified:2021-06-02
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