Associations of placental lncRNA expression with maternal pre-pregnancy BMI and infant birthweight in two birth cohorts

J Dev Orig Health Dis. 2025 May 21;16:e20. doi: 10.1017/S204017442500011X.

ABSTRACT

Pre-pregnancy obesity (ppOB) is linked to pregnancy complications and abnormal fetal growth through placental mechanisms, and long non-coding RNAs (lncRNAs) may play an epigenetic role in these processes. We investigated overall and sex-specific associations of pre-pregnancy body mass index (ppBMI), ppOB, and birthweight with placental lncRNA transcripts in two birth cohorts. Study participants were mother-child dyads recruited to the CANDLE (Memphis, TN)(n = 725) and GAPPS (Seattle and Yakima, WA)(n = 159) cohorts. Maternal ppBMI was assessed at enrollment using interviewer-administered questionnaires. LncRNAs (1,077 and 1,033 for CANDLE and GAPPS, respectively) were sequenced from placental samples collected at birth. Placental lncRNA was regressed on ppBMI, ppOB (ppBMI ≥30kg/m²), or continuous birthweight in cohort-specific weighted linear models controlling for a priori-specified confounders and experimental variables. Potential effect modification by infant-sex was examined in sex-stratified analyses and models including BMI-infant-sex interaction terms. No lncRNA transcripts were significantly associated with ppBMI, ppOB, or birthweight in primary models. Among male infants in CANDLE, expression of three lncRNA transcripts (ERVH48-1, AC139099.1, CEBPA-DT) was associated with ppBMI and one transcript (AC104083.1) with birthweight. In GAPPS, ppBMI was associated with two lncRNA transcripts (AP000879.1 and AL365203.2) among males, and birthweight was associated with 17 lncRNA transcripts (including LINC02709, KANSL1-AS1, DANCR, EPB41L4A-AS1, and GABPB1-AS1) among females. No BMI-infant-sex interactions were observed. Though many of these potential associations are for uncharacterized transcripts, several identified lncRNAs (e.g., ERVH48-1 and CEBPA-DT) have been linked to pathways controlling cancer or placental growth, trophoblast differentiation, and gene expression. These associations warrant validation in future studies.