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

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 JankipersadsingMarc 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

OnderzoeksoutputAcademicpeer review

96 Citaten (Scopus)

Samenvatting

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.

Originele taal-2English
Pagina's (van-tot)379-388
Aantal pagina's10
TijdschriftThe Lancet. Respiratory Medicine
Volume6
Nummer van het tijdschrift5
Vroegere onlinedatum26-feb-2018
DOI's
StatusPublished - mei-2018

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