Placental microRNAs relate to early childhood growth trajectories

Abstract

Background: Poor placental function is a common cause of intrauterine growth restriction, which in turn is associated with increased risks of adverse health outcomes. Our prior work suggests that birthweight and childhood obesity-associated genetic variants functionally impact placental function and that placental microRNA are associated with birthweight. To address the influence of the placenta beyond birth, we assessed the relationship between placental microRNAs and early childhood growth.

Methods: Using the SITAR package, we generated two parameters that describe individual weight trajectories of children (0-5 years) in the New Hampshire Birth Cohort Study (NHBCS, n = 238). Using negative binomial generalized linear models, we identified placental microRNAs that relate to growth parameters (FDR < 0.1), while accounting for sex, gestational age at birth, and maternal parity.

Results: Genes targeted by the six growth trajectory-associated microRNAs are enriched (FDR < 0.05) in growth factor signaling (TGF/beta: miR-876; EGF/R: miR-155, Let-7c; FGF/R: miR-155; IGF/R: Let-7c, miR-155), calmodulin signaling (miR-216a), and NOTCH signaling (miR-629).

Conclusions: Growth-trajectory microRNAs target pathways affecting placental proliferation, differentiation and function. Our results suggest a role for microRNAs in regulating placental cellular dynamics and supports the Developmental Origins of Health and Disease hypothesis that fetal environment can have impacts beyond birth.

Impact: We found that growth trajectory associated placenta microRNAs target genes involved in signaling pathways central to the formation, maintenance and function of placenta; suggesting that placental cellular dynamics remain critical to infant growth to term and are under the control of microRNAs. Our results contribute to the existing body of research suggesting that the placenta plays a key role in programming health in the offspring. This is the first study to relate molecular patterns in placenta, specifically microRNAs, to early childhood growth trajectory.

Fig. 1.. Participation in weight observation collection.

Weights were collected at up to 14 separate time points for each child (x-axis). With the exception of the 1-month (1m) measure, missingness rate (y-axis) was low, meaning that observations at each measurement (obs_age) remained high despite missing data after 12 months (12m, N_age).

Fig. 2.. NHBCS Growth Curves.

Unadjusted growth curves are plotted for all participants in this analysis (N = 238). The mean growth curve, calculated by SITAR, is plotted as a dashed line. The growth curves representing the minimum and maximum average size are plotted in blue and red, respectively. Deviations in average size appear as vertical shifts from the mean curve. The growth curves representing the minimum and maximum growth intensities are plotted in cyan and purple, respectively. Deviations in growth intensity appear as rotations (counter/clockwise) of the mean curve.

Fig. 3.. Differential expression analysis results.

microRNAs with FDR<0.05 in either analysis are listed on the y-axis. Their log₂ fold change for a one percent change in either growth intensity (green) or average size (purple) is on the x-axis. 95% confidence intervals are illustrated with either solid lines. Point size is proportional to −log10(P-value), such that larger points represent smaller p-values.

Fig. 4.. The potential roles of growth trajectory microRNAs in the cellular dynamics of placental trophoblasts.

A terminal placental villous is illustrated in the center of the figure, representing the involved placental cell types from which microRNAs in our study could arise: fetal endothelial cells (FEC), cytotrophoblasts (CTB), syncytiotrophoblasts (STB) and extravillous trophoblasts (EVT).Growth trajectory microRNAs are listed (FDR<0.05 in black, FDR = 0.05–0.1 in gray) along with their influential targets in the processes we predict they may influence (trophoblast stem maintenance, proliferation and differentiation to the syncytiotrophoblast (STB) or extravillous trophoblast (EVT) terminal lineage). microRNAs and their putative targets in the central blue or outer red areas are predicted to encourage or inhibit the given process, respectively. Created with BioRender.com.