TY - JOUR
T1 - DNA methylation in childhood asthma
T2 - an epigenome-wide meta-analysis
AU - the BIOS Consortium
AU - Xu, Cheng Jian
AU - Söderhäll, Cilla
AU - Bustamante, Mariona
AU - Baïz, Nour
AU - Gruzieva, Olena
AU - Gehring, Ulrike
AU - Mason, Dan
AU - Chatzi, Leda
AU - Basterrechea, Mikel
AU - Llop, Sabrina
AU - Torrent, Maties
AU - Forastiere, Francesco
AU - Fantini, Maria Pia
AU - Carlsen, Karin C.Lødrup
AU - Haahtela, Tari
AU - Morin, Andréanne
AU - Kerkhof, Marjan
AU - Merid, Simon Kebede
AU - van Rijkom, Bianca
AU - Jankipersadsing, Soesma A.
AU - Bonder, Marc Jan
AU - Ballereau, Stephane
AU - Vermeulen, Cornelis J.
AU - Aguirre-Gamboa, Raul
AU - de Jongste, Johan C.
AU - Smit, Henriette A.
AU - Kumar, Ashish
AU - Pershagen, Göran
AU - Guerra, Stefano
AU - Garcia-Aymerich, Judith
AU - Greco, Dario
AU - Reinius, Lovisa
AU - McEachan, Rosemary R.C.
AU - Azad, Raf
AU - Hovland, Vegard
AU - Mowinckel, Petter
AU - Alenius, Harri
AU - Fyhrquist, Nanna
AU - Lemonnier, Nathanaël
AU - Pellet, Johann
AU - Auffray, Charles
AU - van der Vlies, Pieter
AU - van Diemen, Cleo C.
AU - Li, Yang
AU - Wijmenga, Cisca
AU - Netea, Mihai G.
AU - Moffatt, Miriam F.
AU - Cookson, William O.C.M.
AU - Anto, Josep M.
AU - Bousquet, Jean
N1 - Publisher Copyright:
© 2018 Elsevier Ltd
PY - 2018/5
Y1 - 2018/5
N2 - 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<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. 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).
AB - 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<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. 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).
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U2 - 10.1016/S2213-2600(18)30052-3
DO - 10.1016/S2213-2600(18)30052-3
M3 - Article
C2 - 29496485
AN - SCOPUS:85042628795
SN - 2213-2600
VL - 6
SP - 379
EP - 388
JO - The Lancet Respiratory Medicine
JF - The Lancet Respiratory Medicine
IS - 5
ER -