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Lung development starts in utero and continues during childhood through to adolescence, reaching its peak in early adulthood. This growth is followed by gradual decline due to physiological lung ageing. Lung-function development can be altered by several host and environmental factors during the life course. As a result, a range of lung-function trajectories exist in the population. Below average trajectories are associated with respiratory, cardiovascular, metabolic, and mental health comorbidities, as well as with premature death. This Review presents progressive research into lung-function trajectories and assists the implementation of this knowledge in clinical practice as an innovative approach to detect poor lung health early, monitor respiratory disease progression, and promote lung health. Specifically, we propose that, similar to paediatric height and weight charts used globally to monitor children's growth, lung-function charts could be used for both children and adults to monitor lung health status across the life course. To achieve this proposal, we introduce our free online Lung Function Tracker tool. Finally, we discuss challenges and opportunities for effective implementation of the trajectory concept at population level and outline an agenda for crucial research needed to support such implementation., Competing Interests: Declaration of interests LL has given lectures sponsored by Chiesi, a non-profit organisation facilitating lifelong learning for health-care providers, and received consulting fees from AstraZeneca, all paid to Ghent University. EM has received lecture fees from Airsonett, ALK, AstraZeneca, Chiesi, and Sanofi. AA has received lecture fees from AstraZeneca, Chiesi, GSK, Menarini, MSD, Sanofi, and Zambon; and research grants from AstraZeneca, GSK, Menarini, and Sanofi. SS has received lecture fees from Vyaire Medical, and consulting fees from Chiasi and NDD. JG-A's institution has received consulting and lecture fees from AstraZeneca (not related to this study); JGA has received lecture fees from Esteve and Chiesi (not related to this study). SCD has received investigator-initiated grants from GlaxoSmithKline and AstraZeneca. HP has received lecture fees (not related to this review) from Teva and Sandoz. AC reports personal fees from Novartis, Sanofi, Stallergenes Greer, AstraZeneca, GlaxoSmithKline, and La Roche-Posay, outside the submitted work. LEGWV has received lecture fees and advisory board fees from GlaxoSmithKline, AstraZeneca, Chiesi, Boehringer, Pulmonx, and Menarini. RF has received lecture fees Chiesi, AstraZeneca, and Zambon, advisory board fees from AstraZeneca, and research grants from AstraZeneca, GSK, Menarini, and Sanofi. JPA has received lecture fees from AstraZeneca. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

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)., (Copyright © 2018 Elsevier Ltd. All rights reserved.)