%0 Journal Article %1 RN124 %A Xu, C. J. %A Söderhäll, C. %A Bustamante, M. %A Baïz, N. %A Gruzieva, O. %A Gehring, U. %A Mason, D. %A Chatzi, L. %A Basterrechea, M. %A Llop, S. %A Torrent, M. %A Forastiere, F. %A Fantini, M. P. %A Carlsen, K. C. L. %A Haahtela, T. %A Morin, A. %A Kerkhof, M. %A Merid, S. K. %A van Rijkom, B. %A Jankipersadsing, S. A. %A Bonder, M. J. %A Ballereau, S. %A Vermeulen, C. J. %A Aguirre-Gamboa, R. %A de Jongste, J. C. %A Smit, H. A. %A Kumar, A. %A Pershagen, G. %A Guerra, S. %A Garcia-Aymerich, J. %A Greco, D. %A Reinius, L. %A McEachan, R. R. C. %A Azad, R. %A Hovland, V. %A Mowinckel, P. %A Alenius, H. %A Fyhrquist, N. %A Lemonnier, N. %A Pellet, J. %A Auffray, C. %A van der Vlies, P. %A van Diemen, C. C. %A Li, Y. %A Wijmenga, C. %A Netea, M. G. %A Moffatt, M. F. %A Cookson, Wocm %A Anto, J. M. %A Bousquet, J. %A Laatikainen, T. %A Laprise, C. %A Carlsen, K. H. %A Gori, D. %A Porta, D. %A Iñiguez, C. %A Bilbao, J. R. %A Kogevinas, M. %A Wright, J. %A Brunekreef, B. %A Kere, J. %A Nawijn, M. C. %A Annesi-Maesano, I. %A Sunyer, J. %A Melén, E. %A Koppelman, G. H. %D 2018 %J Lancet Respir Med %K grapp-caib %N 5 %P 379-388 %R 10.1016/s2213-2600(18)30052-3 %T DNA methylation in childhood asthma: an epigenome-wide meta-analysis %V 6 %X 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).

@article{RN124, abstract = {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).}, added-at = {2022-05-15T19:02:04.000+0200}, author = {Xu, C. J. and Söderhäll, C. and Bustamante, M. and Baïz, N. and Gruzieva, O. and Gehring, U. and Mason, D. and Chatzi, L. and Basterrechea, M. and Llop, S. and Torrent, M. and Forastiere, F. and Fantini, M. P. and Carlsen, K. C. L. and Haahtela, T. and Morin, A. and Kerkhof, M. and Merid, S. K. and van Rijkom, B. and Jankipersadsing, S. A. and Bonder, M. J. and Ballereau, S. and Vermeulen, C. J. and Aguirre-Gamboa, R. and de Jongste, J. C. and Smit, H. A. and Kumar, A. and Pershagen, G. and Guerra, S. and Garcia-Aymerich, J. and Greco, D. and Reinius, L. and McEachan, R. R. C. and Azad, R. and Hovland, V. and Mowinckel, P. and Alenius, H. and Fyhrquist, N. and Lemonnier, N. and Pellet, J. and Auffray, C. and van der Vlies, P. and van Diemen, C. C. and Li, Y. and Wijmenga, C. and Netea, M. G. and Moffatt, M. F. and Cookson, Wocm and Anto, J. M. and Bousquet, J. and Laatikainen, T. and Laprise, C. and Carlsen, K. H. and Gori, D. and Porta, D. and Iñiguez, C. and Bilbao, J. R. and Kogevinas, M. and Wright, J. and Brunekreef, B. and Kere, J. and Nawijn, M. C. and Annesi-Maesano, I. and Sunyer, J. and Melén, E. and Koppelman, G. H.}, biburl = {https://www.bibsonomy.org/bibtex/22f2785c9b6578e7a111bbfd77755a670/nachoricci}, doi = {10.1016/s2213-2600(18)30052-3}, interhash = {028814bbef80c794221c8fcde5926103}, intrahash = {2f2785c9b6578e7a111bbfd77755a670}, issn = {2213-2600}, journal = {Lancet Respir Med}, keywords = {grapp-caib}, number = 5, pages = {379-388}, timestamp = {2022-05-15T19:02:04.000+0200}, title = {DNA methylation in childhood asthma: an epigenome-wide meta-analysis}, type = {Journal Article}, volume = 6, year = 2018 }