DNA Methylation of <i>IGF2DMR</i> and <i>H19</i> Is Associated with Fetal and Infant Growth: The Generation R Study

<div><p>Changes in epigenetic programming of embryonic growth genes during pregnancy seem to affect fetal growth. Therefore, in a population-based prospective birth cohort in the Netherlands, we examined associations between fetal and infant growth and DNA methylation of <i>IGF2DMR</i>, <i>H19</i> and <i>MTHFR</i>. For this study, we selected 69 case children born small-for-gestational age (SGA, birth weight <-2SDS) and 471 control children. Fetal growth was assessed with serial ultrasound measurements. Information on birth outcomes was retrieved from medical records. Infant weight was assessed at three and six months. Methylation was assessed in DNA extracted from umbilical cord white blood cells. Analyses were performed using linear mixed models with DNA methylation as dependent variable. The DNA methylation levels of <i>IGF2DMR</i> and <i>H19</i> in the control group were, median (90% range), 53.6% (44.5–61.6) and 30.0% (25.6–34.2) and in the SGA group 52.0% (43.9–60.9) and 30.5% (23.9–32.9), respectively. The MTHFR region was found to be hypomethylated with limited variability in the control and SGA group, 2.5% (1.4–4.0) and 2.4% (1.5–3.8), respectively. SGA was associated with lower <i>IGF2DMR</i> DNA methylation (β = −1.07, 95% CI −1.93; −0.21, P-value = 0.015), but not with <i>H19</i> methylation. A weight gain in the first three months after birth was associated with lower <i>IGF2DMR</i> DNA methylation (β = −0.53, 95% CI −0.91; −0.16, P-value = 0.005). Genetic variants in the <i>IGF2/H19</i> locus were associated with <i>IGF2DMR</i> DNA methylation (P-value<0.05), but not with <i>H19</i> methylation. Furthermore, our results suggest a possibility of mediation of DNA methylation in the association between the genetic variants and SGA. To conclude, <i>IGF2DMR</i> and <i>H19</i> DNA methylation is associated with fetal and infant growth.</p>