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

<div><p>Context</p><p>Fetal growth involves highly complex molecular pathways. IGF2 is a key paternally expressed growth hormone that is critical for <i>in utero</i> 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, <i>PHLDA</i>2, has a significant negative correlation between its term placental expression and birth weight.</p><p>Objective</p><p>The aim of this study is to address the role in early gestation of expression of <i>IGF1</i>, <i>IGF2</i>, their receptors <i>IGF1R</i> and <i>IGF2R</i>, and <i>PHLDA</i>2 on term birth weight.</p><p>Design</p><p>Real-time quantitative PCR was used to investigate mRNA expression of <i>IGF1</i>, <i>IGF2</i>, <i>IGF1R</i>, <i>IGF2R</i> and <i>PHLDA2</i> 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.</p><p>Results</p><p>Transcript levels of <i>IGF2</i> and <i>IGF2R</i> revealed a significant positive correlation with birth weight (0.009 and 0.04, respectively). No effect was observed for <i>IGF1</i>, <i>IGF1R</i> or <i>PHLDA2</i> and birth weight. Critically, small for gestational age (SGA) neonates had significantly lower <i>IGF2</i> levels than appropriate for gestational age neonates (p = 3·6×10⁻⁷).</p><p>Interpretation</p><p>Our findings show that <i>IGF2</i> 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 <i>in utero</i> growth.</p></div

mRNA expression levels of <i>IGF1/IGF1R</i>, <i>IGF2</i>/<i>IGF2R</i> and <i>IGF2/IGF1R</i> in chorionic villi.

<p>The expression levels of <i>IGF1/IGF1R</i>, <i>IGF2/IGF2R</i> and <i>IGF2/IGF1R</i> after standardization to the endogenous control gene <i>L19</i>, in relation to birth weight corrected for parity, sex, GA at term, maternal BMI and smoking status. No significant association was found for A) the ratio of <i>IGF1</i> to <i>IGF1R</i> (p = 0.76), or for B) the ratio of <i>IGF2</i> to <i>IGF2R</i> (p = 0.93). Significant association was observed for CVS expression of C) the ratio of <i>IGF2</i> to <i>IGF1R</i> (p = 0.005) and birth weight.</p

mRNA expression levels of <i>IGF2</i>, <i>IGF2R</i>, <i>PHLDA2</i>, <i>IGF1</i> and <i>IGF1R</i> in chorionic villi.

<p>The expression levels of <i>IGF2</i>, <i>IGF2R</i>, <i>PHLDA2</i>, <i>IGF1</i> and <i>IGF1R</i> after standardization to the endogenous control gene <i>L19</i>, in relation to birth weight corrected for parity, sex, GA at term, maternal BMI and smoking status. Significant associations were observed for CVS expression of A) <i>IGF2</i> (p = 0.009) and B) <i>IGF2R</i> (p = 0.04). No significant association was found for C) <i>PHLDA2</i> (p = 0.73), for D) <i>IGF1</i> (p = 0.48) or for E) <i>IGF1R</i> (p = 0.08).</p