Division of Epidemiology, Biostatistics, and Environmental Health Sciences, School of Public Health, University of Memphis, Memphis, TN, 38152, USA.
MRC Integrative Epidemiology Unit, University of Bristol, Bristol, BS8 2BN, UK.
Clin Epigenetics. 2021 Jan 6;13(1):5. doi: 10.1186/s13148-020-00992-5.
The 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.
DNA-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.
High and low trajectories of FVC, FEV, and FEV/FVC in each sex were identified. At P < 0.05, DNA-M at 96 distinct CpGs (41 in males) showed associations with FVC, FEV, and FEV/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 P < 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.
The identified CpGs at pre-adolescence have the potential to serve as candidate markers for lung function trajectory prediction and chronic lung diseases.
从青春期前到成年期的肺功能发展模式在呼吸道疾病的发病机制中起着重要作用。遗传研究中肺功能轨迹的不一致发现、DNA 甲基化（DNA-M）的重要性以及青春期在肺功能发育中的关键作用，促使我们研究青春期前的 DNA-M 与肺功能轨迹。本研究调查了儿童时期外周血 DNA-M 与儿童期至青年期肺功能轨迹的全基因组关联。
在 Isle of Wight（IOW）出生队列中，10 岁时测量 DNA-M。10 岁、18 岁和 26 岁时进行肺活量测定。采用基于训练/测试的方法筛选 CpG。应用多变量逻辑回归评估 DNA-M 与青春期前至成年期肺功能轨迹的关系。为了检测 CpG 之间的差异甲基化区域（DMR），进行了 DMR 富集分析。在 Avon Longitudinal Study of Parents and Children（ALSPAC）队列中进一步检测了这些发现。对鉴定出的 CpG 和 DMR 的映射基因进行了通路分析。通过基因表达评估鉴定出的 CpG 的生物学相关性。所有分析均按性别分层。
在每个性别中，均鉴定出 FVC、FEV 和 FEV/FVC 的高和低轨迹。在 P < 0.05 时，96 个独特的 CpG（男性 41 个）的 DNA-M 与 IOW 队列中 FVC、FEV 和 FEV/FVC 轨迹存在关联。在 ALSPAC 中进一步测试了这 95 个 CpG（cg24000797 不合格）；其中 44 个 CpG（男性 19 个）与 IOW 队列中的关联方向相同；有三个 CpG（两个在男性中）得到了复制。男性和女性中，DNA-M 与两个和四个 CpG 的相应基因表达均存在显著关联。在 P < 0.05 时，男性和女性分别鉴定出 23 个和 10 个 DMR。确定了途径；其中一些与肺功能和慢性阻塞性肺疾病有关。
青春期前鉴定出的 CpG 有可能作为肺功能轨迹预测和慢性肺部疾病的候选标志物。
