Epigenetic gestational age acceleration in cord blood is associated with activated inflammatory gene pathways and childhood asthma.

BACKGROUND DNA methylation accurately predicts chronological age, including gestational age (GA). Previous studies have used CpGs on the EPIC or 450K arrays to generate epigenetic clocks for estimating GA.

OBJECTIVE Using the Asthma&Allergy (A&A) array, we estimated GA and calculated GA acceleration (GAA) in cord blood DNA from 2,451 ancestrally diverse participants from seven birth cohorts investigating early life risk factors for asthma and allergic diseases and disease onset in childhood.

METHODS Two gestational epigenetic clocks were constructed: one used GA-associated CpGs in an epigenome-wide association study (EWAS) and a second used CpGs associated with GA in specific cell types. For both, we calculated GAA and tested for associations with six prenatal variables and eight allergy-related childhood outcomes. We then conducted pathway analysis of expressed genes correlated with GAA and validated gene expression signatures in peripheral blood at age 2.

RESULTS Strong correlations between reported GA and estimated GA were observed using the EWAS and the cell-specific clocks (r=0.90 and r=0.83, respectively). Using the cell-specific clock, GAA was associated with two outcomes (higher birthweight, Padj=1.69x10-5; less allergic asthma, Padj=0.025), while the EWAS clock was associated with birthweight (Padj=4.68x10-4). A significant sex by GAA interaction effect on birthweight, with a larger effect size in females, was observed with both clocks (EWAS, Pint=5.77x10-3; cell-specific, Pint=0.021). Cord blood RNA-seq analysis revealed upregulated IL-6 and TNF and downregulated IL-10 signaling pathways associated with GAA, and gene expression in blood at age 2 further revealed associations with asthma at age 7.

CONCLUSION Positive correlations between GAA and inflammatory gene expression and the negative association with allergic asthma suggest that increased expression of inflammatory genes in cord blood and at age 2 is protective against developing asthma. CpGs on the A&A array are accurate predictors of GA, capturing aging aspects specifically related to inflammatory programs.