Periconceptional Maternal Folic Acid Use of 400 µg per Day Is Related to Increased Methylation of the IGF2 Gene in the Very Young Child

Background: Countries worldwide recommend women planning pregnancy to use daily 400 mg of synthetic folic acid in the periconceptional period to prevent birth defects in children. The underlying mechanisms of this preventive effect are not clear, however, epigenetic modulation of growth processes by folic acid is hypothesized. Here, we investigated whether periconceptional maternal folic acid use and markers of global DNA methylation potential (S-adenosylmethionine and S-adenosylhomocysteine blood levels) in mothers and children affect methylation of the insulin-like growth factor 2 gene differentially methylation region (IGF2 DMR) in the child. Moreover, we tested whether the methylation of the IGF2 DMR was independently associated with birth weight. Methodology/Principal Findings: IGF2 DMR methylation in 120 children aged 17 months (SD 0.3) of whom 86 mothers had used and 34 had not used folic acid periconceptionally were studied. Methylation was measured of 5 CpG dinucleotides covering the DMR using a mass spectrometry-based method. Children of mother who used folic acid had a 4.5% higher methylation of the IGF2 DMR than children who were not exposed to folic acid (49.5% vs. 47.4%; p = 0.014). IGF2 DMR methylation of the children also was associated with the S-adenosylmethionine blood level of the mother but not of the child (+1.7% methylation per SD S-adenosylmethionine; p = 0.037). Finally, we observed an inverse independent association between IGF2 DMR methylation and birth weight (-1.7% methylation per SD birthweight; p = 0.034). Conclusions: Periconceptional folic acid use is associated with epigenetic changes in IGF2 in the child that may affect intrauterine programming of growth and development with consequences for health and disease throughout life. These results indicate plasticity of IGF2 methylation by periconceptional folic acid use

<i>IGF2</i> DMR methylation in the child according to maternal periconceptional folic acid use of 400 µg per day.

<p>Linear Mixed Model analysis. Independent absolute methylation of the CpG dinucleotides without adjustments is presented in mean and (standard error).</p

<i>IGF2</i> DMR methylation in the child and independent factors of the mother and the child.

<p>Linear Mixed Model analysis. Data are presented in percentage (standard error) of mean change in relative methylation. For independent quantitative parameters the change in relative methylation is given per SD-change in that parameter. The p-value of the significant association of periconceptional folic acid use and <i>IGF2</i> DMR methylation was additionally adjusted for maternal education. The p-value for the significant association between maternal SAM and IGF2 DMR methylation was also adjusted for maternal education and the SAM concentration of the child. The p-value for the significant association between IGF2 DMR methylation and birth weight was additionally adjusted for periconceptional folic acid use and gestational age at delivery.</p