Paternally Expressed, Imprinted Insulin-Like Growth Factor-2 in Chorionic Villi Correlates Significantly with Birth Weight

Abstract

ContextFetal growth involves highly complex molecular pathways. IGF2 is a key paternally expressed growth hormone that is critical for in utero growth in mice. Its role in human fetal growth has remained ambiguous, as it has only been studied in term tissues. Conversely the maternally expressed growth suppressor, PHLDA2, has a significant negative correlation between its term placental expression and birth weight.ObjectiveThe aim of this study is to address the role in early gestation of expression of IGF1, IGF2, their receptors IGF1R and IGF2R, and PHLDA2 on term birth weight.DesignReal-time quantitative PCR was used to investigate mRNA expression of IGF1, IGF2, IGF1R, IGF2R and PHLDA2 in chorionic villus samples (CVS) (n = 260) collected at 11–13 weeks' gestation. Expression was correlated with term birth weight using statistical package R including correction for several confounding factors.ResultsTranscript levels of IGF2 and IGF2R revealed a significant positive correlation with birth weight (0.009 and 0.04, respectively). No effect was observed for IGF1, IGF1R or PHLDA2 and birth weight. Critically, small for gestational age (SGA) neonates had significantly lower IGF2 levels than appropriate for gestational age neonates (p = 3·6×10−7).InterpretationOur findings show that IGF2 mRNA levels at 12 weeks gestation could provide a useful predictor of future fetal growth to term, potentially predicting SGA babies. SGA babies are known to be at a higher risk for type 2 diabetes. This research reveals an imprinted, parentally driven rheostat for in utero growth.

Effects of maternal nutrition on the expression of genomic imprinted genes in ovine fetuses

“…Such nutrient imbalance has been shown to severely impair fetal and placental development [50]. Interestingly, we found most of the disturbed gene expression were located in the KCNQ1 and IGF2/H19 clusters, consistent with the role of IGF2 as a major fetal growth regulator [54]. Diets of pregnant ewes containing different starch/fiber/protein portions have been shown to change the CpG methylation levels of specific imprinted genes such as IGF2R and H19 [20].…”

Placental 5-methylcytosine and 5-hydroxymethylcytosine patterns associate with size at birth

“…9 Here, we extend these studies to show that this relationship holds across the range of normal birth weight. Previous studies have reported decreased IGF2 expression in placenta from SGA pregnancies, 9,16 which may occur from early on in pregnancy, 35 and studies in mice confirm that IGF2 controls a substantial part of fetal growth. 36 These data are consistent with the predicted effects of IGF2, since paternally expressed genes augment fetal and placental development.…”

The Relationship of Insulin-Like Growth Factor 2 to Fetal Growth and Adiposity

“…The authors found that increased expression of the IGF2 gene in CVS tissue was significantly associated with higher birth weight, highlighting the in utero role of IGF-2 on growth. Furthermore, 19% of infants in this study were classified as SGA and had reduced expression of IGF2 compared to appropriate for gestational age (AGA) infants [36]. …”