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Cheng-Jian Xu, PhD, Cilla Söderhäll, PhD, Mariona Bustamante, PhD, Nour Baïz, PhD, Olena Gruzieva, PhD, Ulrike Gehring, PhD, Dan Mason, PhD, Leda Chatzi, MD, Mikel Basterrechea, MD, Sabrina Llop, PhD, Maties Torrent, PhD, Francesco Forastiere, PhD, Prof Maria Pia Fantini, MD, Prof Karin C Lødrup Carlsen, MD, Prof Tari Haahtela, MD, Andréanne Morin, PhD, Marjan Kerkhof, PhD, Simon Kebede Merid, MSc, Bianca van Rijkom, BSc, Soesma A Jankipersadsing, MSc, Marc Jan Bonder, PhD, Stephane Ballereau, PhD, Cornelis J Vermeulen, PhD, Raul Aguirre-Gamboa, MSc, Johan C de Jongste, MD, Henriette A Smit, PhD, Ashish Kumar, MSc, Prof Göran Pershagen, PhD, Prof Stefano Guerra, MD, Judith Garcia-Aymerich, PhD, Dario Greco, PhD, Lovisa Reinius, PhD, Rosemary R C McEachan, PhD, Raf Azad, FRCP, Vegard Hovland, PhD, Petter Mowinckel, MSc, Harri Alenius, PhD, Nanna Fyhrquist, PhD, Nathanaël Lemonnier, PhD, Johann Pellet, MSc, Charles Auffray, PhD the BIOS Consortium, Pieter van der Vlies, BSc, Cleo C van Diemen, PhD, Yang Li, PhD, Prof Cisca Wijmenga, PhD, Prof Mihai G Netea, PhD, Prof Miriam F Moffatt, PhD, Prof William O C M Cookson, PhD, Prof Josep M Anto, PhD, Prof Jean Bousquet, MD, Prof Tiina Laatikainen, PhD, Prof Catherine Laprise, PhD, Prof Kai-Håkon Carlsen, MD, Davide Gori, MD, Daniela Porta, MSc, Carmen Iñiguez, PhD, Jose Ramon Bilbao, PhD, Manolis Kogevinas, PhD, John Wright, FRCP, Prof Bert Brunekreef, PhD, Prof Juha Kere, PhD, Martijn C Nawijn, PhD, Prof Isabella Annesi-Maesano, PhD, Prof Jordi Sunyer, PhD, Erik Melén, PhD†, Prof Gerard H Koppelman, PhD
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.
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.
27 methylated CpG sites were identified in the discovery analysis. 14 of these CpG sites were replicated and passed genome-wide significance (p<1·14 × 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.
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.
EU and the Seventh Framework Programme (the MeDALL project).