Dataset Information

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

ABSTRACT:

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 cytosine-phosphate-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 FEV₁/FVC, but none for change in FEV₁ 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.

SUBMITTER: Sunny SK

PROVIDER: S-EPMC7140357 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Publications

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

Sunny Shadia Khan SK Zhang Hongmei H Rezwan Faisal I FI Relton Caroline L CL Henderson A John AJ Merid Simon Kebede SK Melén Erik E Hallberg Jenny J Arshad S Hasan SH Ewart Susan S Holloway John W JW

Respiratory research 20200407 1

<h4>Background</h4>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 cytosine-phosphate-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 Cp ...[more]

PMID: 32264874

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Project description:BackgroundThe pattern of lung function development from pre-adolescence to adulthood plays a significant role in the pathogenesis of respiratory diseases. Inconsistent findings in genetic studies on lung function trajectories, the importance of DNA methylation (DNA-M), and the critical role of adolescence in lung function development motivated the present study of pre-adolescent DNA-M with lung function trajectories. This study investigated epigenome-wide associations of DNA-M at cytosine-phosphate-guanine dinucleotide sites (CpGs) at childhood with lung function trajectories from childhood to young adulthood.MethodsDNA-M was measured in peripheral blood at age 10 years in the Isle of Wight (IOW) birth cohort. Spirometry was conducted at ages 10, 18, and 26 years. A training/testing-based method was used to screen CpGs. Multivariable logistic regressions were applied to assess the association of DNA-M with lung function trajectories from pre-adolescence to adulthood. To detect differentially methylated regions (DMRs) among CpGs, DMR enrichment analysis was conducted. Findings were further tested in the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. Pathway analyses were performed on the mapped genes of the identified CpGs and DMRs. Biological relevance of the identified CpGs was assessed with gene expression. All analyses were stratified by sex.ResultsHigh and low trajectories of FVC, FEV1, and FEV1/FVC in each sex were identified. At PBonferroni < 0.05, DNA-M at 96 distinct CpGs (41 in males) showed associations with FVC, FEV1, and FEV1/FVC trajectories in IOW cohort. These 95 CpGs (cg24000797 was disqualified) were further tested in ALSPAC; 44 CpGs (19 in males) of these 95 showed the same directions of association as in the IOW cohort; and three CpGs (two in males) were replicated. DNA-M at two and four CpGs showed significant associations with the corresponding gene expression in males and females, respectively. At PFDR < 0.05, 23 and 10 DMRs were identified in males and females, respectively. Pathways were identified; some of those were linked to lung function and chronic obstructive lung diseases.ConclusionThe identified CpGs at pre-adolescence have the potential to serve as candidate markers for lung function trajectory prediction and chronic lung diseases.

Project description:BackgroundAdolescence is a period characterized by major biological development, which may be associated with changes in DNA methylation (DNA-M). However, it is unknown to what extent DNA-M varies from pre- to post-adolescence, whether the pattern of changes is different between females and males, and how adolescence-related factors are associated with changes in DNA-M.MethodsGenome-scale DNA-M at ages 10 and 18 years in whole blood of 325 subjects (n = 140 females) in the Isle of Wight (IOW) birth cohort was analyzed using Illumina Infinium arrays (450K and EPIC). Linear mixed models were used to examine DNA-M changes between pre- and post-adolescence and whether the changes were gender-specific. Adolescence-related factors and environmental exposure factors were assessed on their association with DNA-M changes. Replication of findings was attempted in the comparable Avon Longitudinal Study of Parents and Children (ALSPAC) cohort.ResultsIn the IOW cohort, after controlling for technical variation and cell compositions at both pre- and post-adolescence, 15,532 cytosine-phosphate-guanine (CpG) sites (of 400,825 CpGs, 3.88%) showed statistically significant DNA-M changes from pre-adolescence to post-adolescence invariant to gender (false discovery rate (FDR) = 0.05). Of these 15,532 CpGs, 10,212 CpGs (66%) were replicated in the ALSPAC cohort. Pathway analysis using Ingenuity Pathway Analysis (IPA) identified significant biological pathways related to growth and development of the reproductive system, emphasizing the importance of this period of transition on epigenetic state of genes. In addition, in IOW, we identified 1179 CpGs with gender-specific DNA-M changes. In the IOW cohort, body mass index (BMI) at age 10 years, age of growth spurt, nonsteroidal drugs use, and current smoking status showed statistically significant associations with DNA-M changes at 15 CpGs on 14 genes such as the AHRR gene. For BMI at age 10 years, the association was gender-specific. Findings on current smoking status were replicated in the ALSPAC cohort.ConclusionAdolescent transition is associated with changes in DNA-M at more than 15K CpGs. Identified pathways emphasize the importance of this period of transition on epigenetic state of genes relevant to cell growth and immune system development.

Project description:The association between newborn DNA methylation (DNAm) and asthma acquisition (AA) during adolescence has been suggested. Lung function (LF) has been shown to be associated with asthma risk and its severity. However, the role of LF in the associations between DNAm and AA is unclear, and it is also unknown whether the association between DNAm and AA is consistent with that between DNAm and LF. We address this question through assessing newborn epigenetic features of preadolescence LF and of AA during adolescence, along with their biological pathways and processes. Our study's primary medical significance lies in advancing the understanding of asthma's early life origins. By investigating epigenetic markers in newborns and their association with lung function in preadolescence, we aim to uncover potential early biomarkers of asthma risk. This could facilitate earlier detection and intervention strategies. Additionally, exploring biological pathways linking early lung function to later asthma development can offer insights into the disease's pathogenesis, potentially leading to novel therapeutic targets.MethodsThe study was based on the Isle of Wight Birth cohort (IOWBC). Female subjects with DNAm data at birth and with no asthma at age 10 years were included (n = 249). The R package ttScreening was applied to identify CpGs potentially associated with AA from 10 to 18 years and with LF at age 10 (FEV1, FVC, and FEV1/FVC), respectively. Agreement in identified CpGs between AA and LF was examined, along with their biological pathways and processes via the R function gometh. We tested the findings in an independent cohort, the Avon Longitudinal Study of Parents and Children (ALSPAC), to examine overall replicability.ResultsIn IOWBC, 292 CpGs were detected with DNAm associated with AA and 1517 unique CpGs for LF (514 for FEV1, 436 for FVC, 408 for FEV1/FVC), with one overlapping CpG, cg23642632 (NCKAP1) between AA and LF. Among the IOWBC-identified CpGs, we further tested in ALSPAC and observed the highest agreement between the two cohorts in FVC with respect to the direction of association and statistical significance. Epigenetic enrichment analyses indicated non-specific connections in the biological pathways and processes between AA and LF.ConclusionsThe present study suggests that FEV1, FVC, and FEV1/FVC (as objective measures of LF) and AA (incidence of asthma) are likely to have their own specific epigenetic features and biological pathways at birth. More replications are desirable to fully understand the complexity between DNAm, lung function, and asthma acquisition.

Dataset Information

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

Background

Methods

Results

Conclusions

Publications

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

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