Newborn DNA-methylation, childhood lung function, and the risks of asthma and COPD across the life course

Dekker, Herman T. den; Burrows, Kimberley; Felix, Janine F.; Salas, Lucas A.; Nedeljković, Ivana; Yao, Jin; Rifas‐Shiman, Sheryl L.; Ruiz‐Arenas, Carlos; Amin, Najaf; Bustamante, Mariona; DeMeo, Dawn L.; Henderson, A. John; Howe, Caitlin G.; Hivert, Marie‐France; Ikram, M. Arfan; Jongste, Johan C. de; Lahousse, Lies; Mandaviya, Pooja R.; Meurs, Joyce B. J. van; Pinart, Mariona; Sharp, Gemma C; Stolk, Lisette; Uitterlinden, André G.; Antó, Josep M.; Litonjua, Augusto A.; Breton, Carrie V.; Brusselle, Guy; Sunyer, Jordi; Smith, George Davey; Relton, Caroline L; Jaddoe, Vincent W. V.; Duijts, Liesbeth

doi:10.1183/13993003.01795-2018

Cited by 56 publications

(35 citation statements)

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“…CpGs cg21584493 is mapped to gene PTPRN2. In a recent study, differentially methylated region (DMR) annotated to PTPRN2 genes was identified for the association with lung function and asthma in children [60]. Findings in Fig.…”

Section: Discussionmentioning

confidence: 99%

“…We suggest that in replication studies agreement in clinical significance should be more important than statistical significance, although it will be most desirable when an agreement is reached in clinical significance accompanied by statistical significance. Among the genes involved in the identified biological processes based on the findings in both ALSPAC and BAMSE cohorts, genes INSIG1, PTCH1, and PTPRN2 have been shown in a range of studies for their involvement in lung development, lung function, and inflammatory airway diseases such as asthma and COPD [54][55][56][57][58][59][60], although most findings were not specifically linked to adolescence. Gene INSIG1 allied with cg15575249 encodes the protein, insulin induced gene 1, which plays a Active smoking at age 10 years in the IOW Cohort was not identified significant role in regulating lipogenesis in alveolar types 2 cells consistent with the roles of sterol regulatory element-binding protein (SREBP)/ sterol cleavageactivating protein in lung lipid synthetic pathways [54].…”

Section: Discussionmentioning

confidence: 99%

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Changes of DNA methylation are associated with changes in lung function during adolescence

et al. 2020

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Background: Adolescence is a significant period for the gender-dependent development of lung function. Prior studies have shown that DNA methylation (DNA-M) is associated with lung function and DNA-M at some cytosinephosphate-guanine dinucleotide sites (CpGs) changes over time. This study examined whether changes of DNA-M at lung-function-related CpGs are associated with changes in lung function during adolescence for each gender, and if so, the biological significance of the detected CpGs. Methods: Genome-scale DNA-M was measured in peripheral blood samples at ages 10 (n = 330) and 18 years (n = 476) from the Isle of Wight (IOW) birth cohort in United Kingdom, using Illumina Infinium arrays (450 K and EPIC). Spirometry was conducted at both ages. A training and testing method was used to screen 402,714 CpGs for their potential associations with lung function. Linear regressions were applied to assess the association of changes in lung function with changes of DNA-M at those CpGs potentially related to lung function. Adolescence-related and personal and family-related confounders were included in the model. The analyses were stratified by gender. Multiple testing was adjusted by controlling false discovery rate of 0.05. Findings were further examined in two independent birth cohorts, the Avon Longitudinal Study of Children and Parents (ALSPAC) and the Children, Allergy, Milieu, Stockholm, Epidemiology (BAMSE) cohort. Pathway analyses were performed on genes to which the identified CpGs were mapped. Results: For females, 42 CpGs showed statistically significant associations with change in FEV 1 /FVC, but none for change in FEV 1 or FVC. No CpGs were identified for males. In replication analyses, 16 and 21 of the 42 CpGs showed the same direction of associations among the females in the ALSPAC and BAMSE cohorts, respectively, with 11 CpGs overlapping across all the three cohorts. Through pathway analyses, significant biological processes were identified that have previously been related to lung function development. Conclusions: The detected 11 CpGs in all three cohorts have the potential to serve as the candidate epigenetic markers for changes in lung function during adolescence in females.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Changes of DNA methylation are associated with changes in lung function during adolescence

et al. 2020

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“…Especially, epigenetic events during the third trimester of pregnancy and the first 6 years of childhood condition the lung to develop chronic inflammatory lung diseases (asthma, COPD) later in life [104,[143][144][145]. Lung tissue specific histone acetylation, mitochondria activity, and disease specific microRNA expression profiles have been reported in asthma patients and were linked to both the immune response and airway wall remodeling [146,147]. Interestingly, these epigenetic events have been reported as being inheritable over three generations by an unknown mechanism [104,107,145,148].…”

Section: Early In Life Epigenetic Events and The Predisposition Of Thmentioning

confidence: 99%

Immunologic and Non-Immunologic Mechanisms Leading to Airway Remodeling in Asthma

Fang

Sun

Roth

2020

IJMS

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Asthma increases worldwide without any definite reason and patient numbers double every 10 years. Drugs used for asthma therapy relax the muscles and reduce inflammation, but none of them inhibited airway wall remodeling in clinical studies. Airway wall remodeling can either be induced through pro-inflammatory cytokines released by immune cells, or direct binding of IgE to smooth muscle cells, or non-immunological stimuli. Increasing evidence suggests that airway wall remodeling is initiated early in life by epigenetic events that lead to cell type specific pathologies, and modulate the interaction between epithelial and sub-epithelial cells. Animal models are only available for remodeling in allergic asthma, but none for non-allergic asthma. In human asthma, the mechanisms leading to airway wall remodeling are not well understood. In order to improve the understanding of this asthma pathology, the definition of “remodeling” needs to be better specified as it summarizes a wide range of tissue structural changes. Second, it needs to be assessed if specific remodeling patterns occur in specific asthma pheno- or endo-types. Third, the interaction of the immune cells with tissue forming cells needs to be assessed in both directions; e.g., do immune cells always stimulate tissue cells or are inflamed tissue cells calling immune cells to the rescue? This review aims to provide an overview on immunologic and non-immunologic mechanisms controlling airway wall remodeling in asthma.

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“…Epigenome wide association studies (EWAS) assessing a genome-wide set of quantifiable modifications of DNA associated with respiratory function or disease, are rapidly emerging. They are promising in increasing our understanding of the influence of smoke and early life exposures into respiratory disease development [3,4]. For example, a recent EWAS identified 59 differentially methylated regions (DMRs) in cord blood associated with childhood lung function, of which 15% was associated with COPD in adults [4].…”

mentioning

confidence: 99%

“…They are promising in increasing our understanding of the influence of smoke and early life exposures into respiratory disease development [3,4]. For example, a recent EWAS identified 59 differentially methylated regions (DMRs) in cord blood associated with childhood lung function, of which 15% was associated with COPD in adults [4]. The 330 genes associated with the 349 identified CpGs in a study among 1454 adults, highlighted pathways of inflammatory responses to stress and external stimuli [5].…”

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confidence: 99%

Epigenetic targets for lung diseases

Lahousse

2019

EBioMedicine

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Newborn DNA-methylation, childhood lung function, and the risks of asthma and COPD across the life course

Abstract: 3 Word count manuscript: 2873Word count abstract: 193

Cited by 56 publications

References 55 publications

Changes of DNA methylation are associated with changes in lung function during adolescence

Changes of DNA methylation are associated with changes in lung function during adolescence

Immunologic and Non-Immunologic Mechanisms Leading to Airway Remodeling in Asthma

Epigenetic targets for lung diseases

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