The aim of this study was to identify placental DNA methylation (DNAm) variations associated with adiposity at 3 years of age. We quantified placental DNAm using the Infinium MethylationEPIC BeadChips. We assessed associations between DNAm at single-CpGs and skinfold thickness using robust linear regression models adjusted for gestational age, child’s sex, age at follow-up and cellular heterogeneity. We sought replication of DNAm association with child adiposity in an independent cohort. We quantified placental mRNA levels for annotated gene using qRT-PCR and tested for correlation with DNAm. Lower DNAm at cg22593959 and cg22436429 was associated with higher adiposity (β = −1.18, q = 0.002 and β = −0.82, q = 0.04). The cg22593959 is located in an intergenic region (chr7q31.3), whereas cg22436429 is within the TFAP2E gene (1p34.3). DNAm at cg22593959 and cg22436429 was correlated with mRNA levels at FAM3C (r_s = −0.279, p = 0.005) and TFAP2E (r_s = 0.216, p = 0.03). In an independent cohort, the association between placental DNAm at cg22593959 and childhood adiposity was of similar strength and direction (β = −3.8 ± 4.1, p = 0.36), yet non-significant. Four genomic regions were also associated with skinfold thickness within FMN1, MAGI2, SKAP2 and BMPR1B genes. We identified placental epigenetic variations associated with adiposity at 3 years of age suggesting that childhood fat accretion patterns might be established during fetal life.

Many women enter pregnancy with overweight and obesity, which are associated with complications for both the expectant mother and her child. MicroRNAs (miRNAs) are short non-coding RNAs that regulate many biological processes, including energy metabolism. Our study aimed to identify first trimester plasmatic miRNAs associated with maternal body mass index (BMI) in early pregnancy. We sequenced a total of 658 plasma samples collected between the 4th and 16th week of pregnancy from two independent prospective birth cohorts (Gen3G and 3D). In each cohort, we assessed associations between early pregnancy maternal BMI and plasmatic miRNAs using DESeq2 R package, adjusting for sequencing run and lane, gestational age, maternal age at the first trimester of pregnancy and parity. A total of 38 miRNAs were associated (FDR q < 0.05) with BMI in the Gen3G cohort and were replicated (direction and magnitude of the fold change) in the 3D cohort, including 22 with a nominal p-value < 0.05. Some of these miRNAs were enriched in fatty acid metabolism-related pathways. We identified first trimester plasmatic miRNAs associated with maternal BMI. These miRNAs potentially regulate fatty acid metabolism-related pathways, supporting the hypothesis of their potential contribution to energy metabolism regulation in early pregnancy.

Plasminogen activator inhibitor (PAI-1) expression has been associated with a higher risk of development of obesity. DNA methylation (DNAm) is an epigenetic mechanism regulating gene transcription and likely involved in the fetal programming of childhood obesity. Our study aimed to assess the associations between PAI-1 gene (SERPINE1) DNAm, plasma PAI-1 levels, and adiposity at five years of age. We analyzed DNAm and anthropometric data from 146 girls and 177 boys from the Gen3G prospective birth cohort. We assessed adiposity using BMI z-scores, waist circumference, total skinfolds, and percentages of total, android, and trunk fat measured by dual-energy radiography (DXA). We estimated blood cell DNAm levels at 15 CpG sites within SERPINE1 using the methylationEPIC array. After correction for multiple testing, we found that lower DNAm in SERPINE1 intron 3 (cg11353706) was associated with greater adiposity levels in girls (waist circumference: r = −0.258, p = 0.002; skinfolds: r = −0.212, p = 0. 013; android fat: r = −0.215, p = 0.015; BMI z-score: r = −0.278, p < 0.001) and that lower DNAm in the SERPINE1 promoter (cg19722814) was associated with higher plasma PAI-1 levels in boys (r = −0.178, p = 0.021). Our study suggests that DNAm levels at the SERPINE1 gene locus are negatively correlated with adiposity, but not with plasma PAI-1 levels, in young girls only.

Maternal blood glucose regulation adaptation to pregnancy aims to support fetal growth but may also lead to the development of gestational diabetes mellitus, the most common pregnancy complication. MiRNAs are small RNA molecules secreted and stable in the blood, where they could have paracrine hormone-like functions (ribo-hormone) and regulate metabolic processes including fetal growth and glucose metabolism. The objective of this study was to identify plasmatic microRNA (miRNAs) measured during the first trimester of pregnancy that were associated with glucose levels during a 75 g oral glucose tolerance test (OGTT) at ~26 weeks of pregnancy. miRNAs were quantified using next-generation sequencing in 444 pregnant women and replicated in an independent cohort of 106 pregnant women. MiRNAs associated with glucose levels were identified with the DESeq2 package. We identified 24 miRNAs associated with fasting glycemia, of which 18 were common to both cohorts (q-value < 0.1). However, no association was found between miRNAs and 1 h or 2 h post OGTT glycemia. To conclude, we identified 18 miRNAs early in pregnancy that were associated with fasting blood glucose measured 3 months later. Our findings offer new insights into the mechanisms involved in fasting glucose homeostasis regulation in pregnancy, which is critical to understanding how gestational diabetes develops.