(OR02-06-25) Maternal Prenatal Traits and Child Hepatic Fat Are Associated With Umbilical Cord Blood DNA Methylation in the Healthy Start Cohort

Objectives: Metabolic dysfunction-associated steatotic liver disease has risen alongside childhood obesity with an estimated prevalence of 13-24% in the US. The intrauterine environment may prime excess hepatic fat accrual in offspring. Our study sought to determine the role of epigenetics in the link between maternal prenatal exposures and child hepatic fat (HF).

Methods: We enrolled 1,410 mother-child dyads in the Healthy Start Study. Maternal prenatal traits were dietary quality, assessed with the Healthy eating index (HEI) and relative Mediterranean diet score (RMED), physical activity, and cardiometabolic markers measured in mid-to-late pregnancy (median 27 weeks gestation). We measured DNA methylation in umbilical cord blood with the Illumina 450K array. In a subset of participants, we measured child HF in early- and mid-childhood (n=131, mean age 5.0±0.8 yrs; and n=63, mean age 8.9±0.6 yrs) by MRI. We tested the association of differentially methylated regions (DMR) with maternal traits and child HF separately. Models were adjusted for maternal age, pre-pregnancy BMI, gestational age at birth, child age at MRI, and sex of child as appropriate, followed by Šidák multiple testing correction. Next, we determined which maternal traits independently correlated with child HF (Pearson). For significant correlations, we then assessed overlap of DMRs associated with the maternal trait and child HF.

Results: 630 DMRs were associated with various maternal traits: HEI, RMED, prenatal vitamin intake, physical activity, hba1c, total cholesterol, LDL, HDL, triglycerides (TG), fasting glucose, HOMA-IR, and TNF-α (adj p< 0.05). Separately, 2 DMRs (adj p≤0.03) and 12 DMRs (adj p< 0.002) were associated with child HF at 5 and 9 years, respectively. Amongst maternal traits independently correlated with child HF, 2 were associated with DMRs also associated with child HF. For example, maternal TG correlated with child HF at age 5, while TG and child HF were both associated with a DMR localizing to TACSTD2. This gene is implicated as a marker of liver progenitor cells.

Conclusions: These results suggest modifiable maternal prenatal factors may have lasting impacts on child hepatic fat, potentially driven by epigenetic modulation in utero.

Funding Sources: NIH ECHO, Healthy Start Study, CCTSI