Priyadarshini Kachroo, PhD
Brigham and Women's Hospital
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
Dr. Dawn L. DeMeo
“Rationale: Lung function deficit has its origins in early life. A comprehensive view of the sex-specific associations between DNA methylation and lung function during childhood is necessary.
Methods: We measured whole blood DNAm using Infinium MethylationEPIC BeadChip from two childhood asthma cohorts: Childhood Asthma Management Program (CAMP; 423 boys, 280 girls, mean-age 12.9y) and the Genetic Epidemiology of Asthma in Costa Rica Study (CRA; 467 boys, 321 girls, mean-age 9.3y) to identify sex-specific 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)). Findings were validated in The Vitamin D Antenatal Asthma Reduction Trial (VDAART) using cord blood DNAm (304 boys, 268 girls).
Results: We identified a higher variability and percentage of differentially methylated CpGs in girls compared to boys for all lung function (FDR<0.05) outcomes. We identified sex-specific associations with consistent direction of effect between cord blood DNAm at birth and lung function with those during childhood in CRA at 1 CpG with FEV1; 2 CpGs for FEV1/FVC; 3 CpGs for FEF25-75/FVC. Similarly, 5 sex-specific CpGs validated for FEV1, 2 CpGs for FVC, 8 CpGs for FEV1/FVC, 6 CpGs for FEF25-75/FVC between VDAART and CAMP. Within each cohort, several CpGs showed opposite direction of effect between males and females for FEV1/FVC and FEF25-75/FVC that showed enrichment in endocrine and immune processes and pathways including mTOR signaling, autophagy, Insulin signaling and GnRH secretion.
Conclusion: We identified sex-specific DNA methylation patterns predictive of lung function at birth and during adolescence. Epigenetic changes spanning the puberty window provide mechanistic insights into fetal programming and potential targets for preventative interventions against sex-differences in lung function decline and asthma progression in later life.”