DNA methylation in childhood asthma: an epigenome-wide meta-analysis

Xu, C-J., Söderhäll, C., Bustamante, M., Baïz, N., Gruzieva, O., Gehring, U., Mason, D., Chatzi, L., Basterrechea, M., Llop, S., Torrent, M., Forastiere, F., Fantini, M. P., Carlsen, K. C. L., Haahtela, T., Morin, A., Kerkhof, M., Merid, S. K., van Rijkom, B., Jankipersadsing, S. A., Bonder, M. J., Ballereau, S., Vermeulen, C. J., Aguirre-Gamboa, R., de Jongste, J. C., Smit, H. A., Kumar, A., Pershagen, G., Guerra, S., Garcia-Aymerich, J., Greco, D., Reinius, L., McEachan, R. R. C., Azad, R., Hovland, V., Mowinckel, P., Alenius, H., Fyhrquist, N., Lemonnier, N., Pellet, J., Auffray, C., van der Vlies, P., van Diemen, C. C., Li, Y., Wijmenga, C., Netea, M. G., Moffatt, M. F., Cookson, W. O. C. M., Nawijn, M. C., Koppelman, G. H. & BIOS Consortium, May-2018, In : The Lancet. Respiratory Medicine. 6, 5, p. 379-388 10 p.

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  • DNA methylation in childhood asthma

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  • Cheng-Jian Xu
  • Cilla Söderhäll
  • Mariona Bustamante
  • Nour Baïz
  • Olena Gruzieva
  • Ulrike Gehring
  • Dan Mason
  • Leda Chatzi
  • Mikel Basterrechea
  • Sabrina Llop
  • Maties Torrent
  • Francesco Forastiere
  • Maria Pia Fantini
  • Karin C Lødrup Carlsen
  • Tari Haahtela
  • Andréanne Morin
  • Marjan Kerkhof
  • Simon Kebede Merid
  • Bianca van Rijkom
  • Soesma A Jankipersadsing
  • Marc Jan Bonder
  • Stephane Ballereau
  • Cornelis J Vermeulen
  • Raul Aguirre-Gamboa
  • Johan C de Jongste
  • Henriette A Smit
  • Ashish Kumar
  • Göran Pershagen
  • Stefano Guerra
  • Judith Garcia-Aymerich
  • Dario Greco
  • Lovisa Reinius
  • Rosemary R C McEachan
  • Raf Azad
  • Vegard Hovland
  • Petter Mowinckel
  • Harri Alenius
  • Nanna Fyhrquist
  • Nathanaël Lemonnier
  • Johann Pellet
  • Charles Auffray
  • Pieter van der Vlies
  • Cleo C van Diemen
  • Yang Li
  • Cisca Wijmenga
  • Mihai G Netea
  • Miriam F Moffatt
  • William O C M Cookson
  • Martijn C Nawijn
  • Gerard H Koppelman
  • BIOS Consortium

Background DNA methylation profiles associated with childhood asthma might provide novel insights into disease pathogenesis. We did an epigenome-wide association study to assess methylation profiles associated with childhood asthma.

Methods We did a large-scale epigenome-wide association study (EWAS) within the Mechanisms of the Development of ALLergy (MeDALL) project. We examined epigenome-wide methylation using Illumina Infinium Human Methylation450 BeadChips (450K) in whole blood in 207 children with asthma and 610 controls at age 4-5 years, and 185 children with asthma and 546 controls at age 8 years using a cross-sectional case-control design. After identification of differentially methylated CpG sites in the discovery analysis, we did a validation study in children (4-16 years; 247 cases and 2949 controls) from six additional European cohorts and meta-analysed the results. We next investigated whether replicated CpG sites in cord blood predict later asthma in 1316 children. We subsequently investigated cell-type-specific methylation of the identified CpG sites in eosinophils and respiratory epithelial cells and their related gene-expression signatures. We studied cell-type specificity of the asthma association of the replicated CpG sites in 455 respiratory epithelial cell samples, collected by nasal brushing of 16-year-old children as well as in DNA isolated from blood eosinophils (16 with asthma, eight controls [age 2-56 years]) and compared this with whole-blood DNA samples of 74 individuals with asthma and 93 controls (age 1-79 years). Whole-blood transcriptional profiles associated with replicated CpG sites were annotated using RNA-seq data of subsets of peripheral blood mononuclear cells sorted by fluorescence-activated cell sorting.

Findings 27 methylated CpG sites were identified in the discovery analysis. 14 of these CpG sites were replicated and passed genome-wide significance (p

Interpretation Reduced whole-blood DNA methylation at 14 CpG sites acquired after birth was strongly associated with childhood asthma. These CpG sites and their associated transcriptional profiles indicate activation of eosinophils and cytotoxic T cells in childhood asthma. Our findings merit further investigations of the role of epigenetics in a clinical context.

Original languageEnglish
Pages (from-to)379-388
Number of pages10
JournalThe Lancet. Respiratory Medicine
Issue number5
Early online date26-Feb-2018
Publication statusPublished - May-2018



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