Epigenome-wide meta-analysis of DNA methylation and childhood asthma.

Journal Article (Journal Article)

BACKGROUND: Epigenetic mechanisms, including methylation, can contribute to childhood asthma. Identifying DNA methylation profiles in asthmatic patients can inform disease pathogenesis. OBJECTIVE: We sought to identify differential DNA methylation in newborns and children related to childhood asthma. METHODS: Within the Pregnancy And Childhood Epigenetics consortium, we performed epigenome-wide meta-analyses of school-age asthma in relation to CpG methylation (Illumina450K) in blood measured either in newborns, in prospective analyses, or cross-sectionally in school-aged children. We also identified differentially methylated regions. RESULTS: In newborns (8 cohorts, 668 cases), 9 CpGs (and 35 regions) were differentially methylated (epigenome-wide significance, false discovery rate < 0.05) in relation to asthma development. In a cross-sectional meta-analysis of asthma and methylation in children (9 cohorts, 631 cases), we identified 179 CpGs (false discovery rate < 0.05) and 36 differentially methylated regions. In replication studies of methylation in other tissues, most of the 179 CpGs discovered in blood replicated, despite smaller sample sizes, in studies of nasal respiratory epithelium or eosinophils. Pathway analyses highlighted enrichment for asthma-relevant immune processes and overlap in pathways enriched both in newborns and children. Gene expression correlated with methylation at most loci. Functional annotation supports a regulatory effect on gene expression at many asthma-associated CpGs. Several implicated genes are targets for approved or experimental drugs, including IL5RA and KCNH2. CONCLUSION: Novel loci differentially methylated in newborns represent potential biomarkers of risk of asthma by school age. Cross-sectional associations in children can reflect both risk for and effects of disease. Asthma-related differential methylation in blood in children was substantially replicated in eosinophils and respiratory epithelium.

Full Text

Duke Authors

Cited Authors

  • Reese, SE; Xu, C-J; den Dekker, HT; Lee, MK; Sikdar, S; Ruiz-Arenas, C; Merid, SK; Rezwan, FI; Page, CM; Ullemar, V; Melton, PE; Oh, SS; Yang, IV; Burrows, K; Söderhäll, C; Jima, DD; Gao, L; Arathimos, R; Küpers, LK; Wielscher, M; Rzehak, P; Lahti, J; Laprise, C; Madore, A-M; Ward, J; Bennett, BD; Wang, T; Bell, DA; BIOS consortium, ; Vonk, JM; Håberg, SE; Zhao, S; Karlsson, R; Hollams, E; Hu, D; Richards, AJ; Bergström, A; Sharp, GC; Felix, JF; Bustamante, M; Gruzieva, O; Maguire, RL; Gilliland, F; Baïz, N; Nohr, EA; Corpeleijn, E; Sebert, S; Karmaus, W; Grote, V; Kajantie, E; Magnus, MC; Örtqvist, AK; Eng, C; Liu, AH; Kull, I; Jaddoe, VWV; Sunyer, J; Kere, J; Hoyo, C; Annesi-Maesano, I; Arshad, SH; Koletzko, B; Brunekreef, B; Binder, EB; Räikkönen, K; Reischl, E; Holloway, JW; Jarvelin, M-R; Snieder, H; Kazmi, N; Breton, CV; Murphy, SK; Pershagen, G; Anto, JM; Relton, CL; Schwartz, DA; Burchard, EG; Huang, R-C; Nystad, W; Almqvist, C; Henderson, AJ; Melén, E; Duijts, L; Koppelman, GH; London, SJ

Published Date

  • June 2019

Published In

Volume / Issue

  • 143 / 6

Start / End Page

  • 2062 - 2074

PubMed ID

  • 30579849

Pubmed Central ID

  • PMC6556405

Electronic International Standard Serial Number (EISSN)

  • 1097-6825

Digital Object Identifier (DOI)

  • 10.1016/j.jaci.2018.11.043


  • eng

Conference Location

  • United States