Placental miR-3940-3p is associated with maternal insulin resistance in late pregnancy

Context: An increase in maternal insulin resistance (IR) during pregnancy is essential for normal fetal growth. The mechanisms underlying this metabolic adaptation to pregnancy are poorly understood. Placenta factors are believed to instigate and maintain these metabolic changes, as IR decreases shortly after delivery. Methylation of placental gene loci that are common targets for miRNAs, are associated with maternal IR. Objective: We hypothesized that placental miRNAs targeting methylated loci are associated with maternal IR during late pregnancy. Methods: Placentas were collected from 132 elective cesarean sections and fasting maternal HOMA-IR at delivery was calculated. Placental miRNA expression was measured via small RNA-sequencing in a subset of 40 placentas selected by maternal pre-gravid BMI and neonatal adiposity. Five miRNAs that correlated with maternal HOMA-IR and were previously identified as targeting methylated genes were selected for validation in all 132 placenta samples via RT-qPCR. Multilinear regression was used to adjust for relevant clinical variables. Results: Median maternal age was 27.5 years, with a median pre-pregnancy BMI of 24.7 kg/m2, and median HOMA-IR of 2.9. Among the five selected miRNA, near delivery maternal HOMA-IR correlated with the placental expression of miRNA-371b-3p (r=0.25; p=0.008) and miRNA-3940-3p (r=0.32; p=0.0004) across the 132 individuals. After adjustment for confounding variables, placental miRNA-3940-3p expression remained significantly associated with HOMA-IR (β=0.16; p=0.03). Conclusion: Placental miRNA-3940-3p was associated with maternal IR in near delivery. This placental miRNA may have an autocrine or paracrine effect - regulating placental genes which play a role in modulating maternal IR.