Priyadarshini Kachroo, PhD
Channing Division of Network Medicine
Priyadarshini Kachroo*, Siqin Li, Julian Hecker, Vincent Carey, Augusto A. Litonjua, Juan C. Celedón, Scott T. Weiss, Dawn L. DeMeo
Dawn L. DeMeo
Rationale: Lung function deficit has its origins in early life. There is limited understanding of the association between DNA-methylation and lung function during childhood.
Methods: We measured whole blood DNA-methylation using Infinium MethylationEPIC BeadChip from two childhood asthma cohorts: Childhood Asthma Management Program (CAMP; n=703, mean-age 12.9y) and Genetic Epidemiology of Asthma in Costa Rica Study (CRA; n=788, mean-age 9.3y) for discovery and replication of CpGs predictive of lung function (forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), their ratio (FEV1/FVC), and forced expiratory flow at 25–75% of forced vital capacity (FEF25-75/FVC)). Lung function trajectories were defined previously and examined in CAMP. Findings were validated in The Vitamin D Antenatal Asthma Reduction Trial (VDAART) using cord blood DNA-methylation (n=572) and investigated for associations with asthma outcomes.
Results: We identified several differentially methylated CpGs and regions (≥4-CpGs) for all lung function (FDR<0.05), trajectory and asthma (less stringent p-value<1e-03) outcomes. Of all, 990 CpGs and 9 regions for FEV1/FVC and 310 CpGs and 8 regions for FEF25-75/FVC overlapped between CAMP and CRA; majority were hypermethylated and showed consistent direction of effect (99.6%). Six CpG-associations with FEV1/FVC from CAMP and CRA also validated in VDAART predictive of asthma outcome at age 6 only mapping to MED25, NOLC1, SWAP70, GPI, RALA, ROR1 genes and implicated in allergic asthma and eosinophilia from EWAS catalogue. Top significantly enriched disease terms included vital capacity, inflammatory disorders, and smoking behaviors whereas Bronchopulmonary Dysplasia was unique to CRA. Top enriched pathways included Cholinergic synapse, Sphingolipid signaling, Phosphatidylinositol signaling, T-cell receptor and PI3K-Akt signaling for hyper-methylated CpGs and Rap1 signaling and adherens junction for hypomethylated CpGs.
Conclusion: Lung function patterns associated with DNA-methylation at birth and during childhood provide mechanistic insights into fetal programming and potential targets for preventative interventions against lung function decline and asthma progression.
A comprehensive view of the associations between DNA methylation and lung function during childhood is necessary and in diverse populations. Our aim was to characterize DNA methylation differences predictive of lung function within and between multiethnic cohorts. Our findings not only highlight the distinct asthma disease etiology but also provide mechanistic insights into epigenetic programming at birth and adolescence and potential biological processes contributing to sex-differences in lung function decline and asthma progression in later life.