Epigenetic gestational age acceleration in cord blood is associated with activated inflammatory gene pathways and childhood asthma.
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- Record sourced from PubMed, PMID 42302975.
- Also identified by DOI 10.1016/j.jaci.2026.06.003.
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Abstract
DNA methylation accurately predicts chronological age, including gestational age (GA). Previous studies have used 5'-C-phosphate-G-3' sites (CpGs) on the EPIC or 450K arrays to generate epigenetic clocks for estimating GA. Using the Asthma&Allergy array, we estimated GA and calculated GA acceleration (GAA) in cord blood DNA from 2451 ancestrally diverse participants from 7 birth cohorts investigating early life risk factors for asthma and allergic diseases and disease onset in childhood. 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 6 prenatal variables and 8 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 years. Strong correlations between reported GA and estimated GA were observed using the EWAS and the cell-specific clocks (r = 0.90 and 0.83, respectively). Using the cell-specific clock, GAA was associated with 2 outcomes (higher birthweight, P<sub>adj</sub> = 1.69 × 10<sup>-5</sup>; less allergic asthma, P<sub>adj</sub> = .025), while the EWAS clock was associated with birthweight (P<sub>adj</sub> = 4.68 × 10<sup>-4</sup>). A significant sex-by-GAA interaction effect on birthweight, with a larger effect size in females, was observed with both clocks (EWAS, P<sub>int</sub> = 5.77 × 10<sup>-3</sup>; cell-specific, P<sub>int</sub> = .021). Cord blood RNA-sequencing analysis revealed upregulated IL6 and TNF and downregulated IL10 signaling pathways associated with GAA, and gene expression in blood at age 2 years further revealed associations with asthma at age 7 years. 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 years is protective against developing asthma. CpGs on the Asthma&Allergy array are accurate predictors of GA, capturing aging aspects specifically related to inflammatory programs.