Abstract
BackgroundAdolescence 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.MethodsGenome-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.ResultsFor 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.ConclusionsThe 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.
Highlights
Adolescence is a significant period for the gender-dependent development of lung function
To identify candidate cytosinephosphate-guanine dinucleotide sites (CpGs) potentially associated with lung function at ages 10 and 18 years, we applied ttScreening to the 402,714 CpGs in each gender
Of the 42 CpGs examined, DNA methylation (DNA-M) changes at 16 CpGs (Table 3) showed consistent associations with Forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) changes compared to those observed in the Isle of Wight (IOW) cohort (Fig. 2, Table 3), not statistically significant at the 0.05 level
Summary
Adolescence is a significant period for the gender-dependent development of lung function. The period from childhood to adolescence is associated with rapid somatic growth and incorporates a range of gender-dependent physiological and behavioral changes, including hormonal, height and body mass index (BMI) changes, possible use of oral contraceptives, and possible initiation of nicotine use [1, 2] This period is significant for the development of lung function as it represents a phase of dramatic growth from childhood to adolescence to reach a maximal level of lung function in early adulthood [3,4,5]. In our recent genome-wide study, we identified more than 10 K CpGs where DNA-M significantly changes over the adolescence period, and at some CpGs, such changes were gender-dependent [23]
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