Kachroo Priyadarshini, Shutta Katherine H, Maiorino Enrico, Moll Matthew, Hecker Julian, Carey Vincent, McGeachie Michael J, Litonjua Augusto A, Celedón Juan C, Weiss Scott T, DeMeo Dawn L
School of Health Professions, Department of Health Informatics, Rutgers The State University of New Jersey, NJ, USA.
Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
bioRxiv. 2025 May 14:2025.05.12.653131. doi: 10.1101/2025.05.12.653131.
Lung function deficits may be caused by early life epigenetic programming. Early childhood studies are necessary to understand life-course trends in lung diseases.
We aimed to examine whether DNA-methylation at birth and childhood is associated with lung function growth.
We measured DNA-methylation in leukocytes from participants in two childhood asthma cohorts (CAMP [n=703, mean-age 12.9 years] and GACRS [n=788, mean-age 9.3 years]) and cord blood from participants in the VDAART study (n=572) to identify CpGs and pathways associated with lung function.
We identified 1,049 consistent differentially methylated CpGs (608 relatively hypermethylated) across all three studies (FDR-P<0.05). Relatively hypomethylated CpGs were enriched for gluconeogenesis, cell adhesion and VEGF signaling. Relatively hypermethylated CpGs were enriched for Hippo, B-cell and growth hormone receptor signaling. Functional enrichment suggested potential regulatory roles for active enhancers and histone modifications. Additionally, enrichment in PI3K/AKT and Notch pathways in males and enrichment in hormonal pathways in females was identified. Gaussian graphical models identified sex-differential DNA-methylation nodes and hub scores at birth and childhood. Integrating with previously identified polygenic risk scores for asthma and drug-target enrichment identified seven robust genes including , and with known associations as biomarkers for asthma severity and drug targets for airway inflammation.
Epigenetic variability from birth through puberty provides mechanistic insights into fetal programming of developmental and immune pathways associated with lung function. These early life observations reveal potential targets for mitigating risk for lung function decline and asthma progression in later life.
肺功能缺陷可能是由生命早期的表观遗传编程引起的。有必要开展幼儿期研究以了解肺部疾病的生命历程趋势。
我们旨在研究出生时和儿童期的DNA甲基化是否与肺功能增长相关。
我们测量了两个儿童哮喘队列（CAMP [n = 703，平均年龄12.9岁]和GACRS [n = 788，平均年龄9.3岁]）参与者白细胞中的DNA甲基化，以及VDAART研究（n = 572）参与者脐带血中的DNA甲基化，以确定与肺功能相关的CpG和信号通路。
我们在所有三项研究中确定了1049个一致的差异甲基化CpG（608个相对高甲基化）（FDR-P<0.05）。相对低甲基化的CpG在糖异生、细胞粘附和VEGF信号通路中富集。相对高甲基化的CpG在Hippo、B细胞和生长激素受体信号通路中富集。功能富集表明活性增强子和组蛋白修饰具有潜在的调节作用。此外，还发现男性中PI3K/AKT和Notch信号通路富集，女性中激素信号通路富集。高斯图形模型确定了出生时和儿童期的性别差异DNA甲基化节点和中心分数。与先前确定的哮喘多基因风险评分和药物靶点富集相结合，确定了七个稳健的基因，包括 、 和 ，它们具有已知的关联，可作为哮喘严重程度的生物标志物和气道炎症的药物靶点。
从出生到青春期的表观遗传变异性为与肺功能相关的发育和免疫途径的胎儿编程提供了机制性见解。这些生命早期的观察结果揭示了降低晚年肺功能下降和哮喘进展风险的潜在靶点。
