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Article Dans Une Revue The Lancet Respiratory Medicine Année : 2018

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

Davide Gori
  • Fonction : Auteur
Daniela Porta
  • Fonction : Auteur
Carmen Iñiguez
  • Fonction : Auteur
Jose Ramon Bilbao
  • Fonction : Auteur
John Wright
  • Fonction : Auteur
Bert Brunekreef
Martijn C. Nawijn
  • Fonction : Auteur
Gerard H. Koppelman
Cheng-Jian Xu
  • Fonction : Auteur
Cilla Söderhäll
  • Fonction : Auteur
Ulrike Gehring
Dan Mason
  • Fonction : Auteur
Mikel Basterrechea
  • Fonction : Auteur
Sabrina Llop
  • Fonction : Auteur
Maties Torrent
  • Fonction : Auteur
Francesco Forastiere
Maria Pia Fantini
  • Fonction : Auteur
Karin C. Lødrup Carlsen
  • Fonction : Auteur
Tari Haahtela
Marjan Kerkhof
  • Fonction : Auteur
Simon Kebede Merid
  • Fonction : Auteur
Bianca Van Rijkom
  • Fonction : Auteur
Soesma A. Jankipersadsing
  • Fonction : Auteur
Marc Jan Bonder
  • Fonction : Auteur
Cornelis J. Vermeulen
  • Fonction : Auteur
Raul Aguirre-Gamboa
  • Fonction : Auteur
Johan C. De Jongste
  • Fonction : Auteur
Henriette A. Smit
  • Fonction : Auteur
Ashish Kumar
Dario Greco
  • Fonction : Auteur
Lovisa Reinius
  • Fonction : Auteur
Rosemary R. C. Mceachan
  • Fonction : Auteur
Raf Azad
  • Fonction : Auteur
Vegard Hovland
  • Fonction : Auteur
Petter Mowinckel
  • Fonction : Auteur
Harri Alenius
  • Fonction : Auteur
Nanna Fyhrquist
  • Fonction : Auteur
Charles Auffray
  • Fonction : Auteur
Bios Consortium
  • Fonction : Auteur
Pieter van Der Vlies
  • Fonction : Auteur
Cleo C. Van Diemen
  • Fonction : Auteur
Yang Li
  • Fonction : Auteur
Cisca Wijmenga
  • Fonction : Auteur
Miriam F. Moffatt
  • Fonction : Auteur
William O. C. M. Cookson
  • Fonction : Auteur
Josep M. Anto
  • Fonction : Auteur
Tiina Laatikainen
  • Fonction : Auteur
Kai-H\r Akon Carlsen
  • Fonction : Auteur

Résumé

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\textless1\textperiodcentered14 \texttimes 10-7) after meta-analysis. Consistently lower methylation levels were observed at all associated loci across childhood from age 4 to 16 years in participants with asthma, but not in cord blood at birth. All 14 CpG sites were significantly associated with asthma in the second replication study using whole-blood DNA, and were strongly associated with asthma in purified eosinophils. Whole-blood transcriptional signatures associated with these CpG sites indicated increased activation of eosinophils, effector and memory CD8 T cells and natural killer cells, and reduced number of naive T cells. Five of the 14 CpG sites were associated with asthma in respiratory epithelial cells, indicating cross-tissue epigenetic effects. 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. FUNDING: EU and the Seventh Framework Programme (the MeDALL project).

Dates et versions

hal-02345946 , version 1 (04-11-2019)

Identifiants

Citer

Davide Gori, Daniela Porta, Carmen Iñiguez, Jose Ramon Bilbao, Manolis Kogevinas, et al.. DNA methylation in childhood asthma: an epigenome-wide meta-analysis. The Lancet Respiratory Medicine, 2018, 6 (5), pp.379--388. ⟨10.1016/S2213-2600(18)30052-3⟩. ⟨hal-02345946⟩
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