Maternal plasma folate controls epigenome of newborns

Maternal plasma folate controls epigenome of newborns

Folate (vitamin B9) is vital for fetal development. Folic acid supplementation at 0.4 mg per day or higher is recommended worldwide before and in the very early stages of pregnancy to reduce the incidence of neural tube defects (NTDs). Over 50 countries have introduced programs to fortify the food supply with folic acid to increase folate levels in women of childbearing age.

Rates of NTDs have clearly decreased following fortification and there is increasing interest in the possibility that higher maternal folate prevents additional birth defects including oral clefts, cardiac defects and others. A large international trial has been launched of supplementation with 4 mg versus the standard 0.4 mg to attempt to address these questions.

Other beneficial effects of higher maternal folate levels have been reported in humans. These include reduced risk of low birth weight, pre-term delivery, language delay, leukaemia, childhood brain tumors and autism, although the evidence is inconsistent. Higher folic acid intake during pregnancy has been associated with an increased risk of childhood retinoblastoma and early respiratory illness.

The mechanisms whereby folic acid prevents NTDs and potentially other birth defects and later health outcomes are poorly understood but could involve epigenetic changes. Folate is a critical component in the one-carbon metabolism pathway providing methyl groups for a range of biochemical reactions, including methylation of DNA. DNA methylation is an important epigenetic determinant of gene expression, and differential methylation has been associated with multiple diseases. Periconceptional maternal folate levels may alter methylation patterns established in utero that are vital for fetal development, which could impact later health outcomes in the offspring.

In mouse models, in utero dietary methyl donor supplementation has been associated with altered methylation patterns and disease phenotypes. The brains of human fetuses with NTDs had lower global methylation compared with controls, which was positively correlated with maternal folate levels. With respect to gene-specific differential methylation, perinatal folate has also been associated with differential methylation in specific imprinted genes, such as IGF2 and H19, in offspring, but reported results are inconsistent. The only published study using a platform with reasonable genome-wide coverage, the Illlumina HumanMethyl450 Beadchip (450 K), investigated 23 subjects and reported that folic acid supplementation during pregnancy was related to differential methylation upstream of the gene ZFP57, which plays a central role in the regulation and maintenance of imprinting.

Some countries, such as Norway and the Netherlands, do not fortify the food supply with folic acid. These populations may be particularly useful for examining the biological implications of periconceptional folic acid supplementation on offspring health, as greater variability in the dose and the source of folate may exist compared with fortified populations.

To better understand the biological implications of folate status on the developing fetus, researchers examined the association between maternal plasma folate during pregnancy and epigenome-wide differential DNA methylation in newborn cord blood using the Illumina HumanMethyl450 (450 K) Beadchip. Authors included 1,988 newborns from two European pregnancy cohorts.

Researchers report the combined covariate-adjusted results using meta-analysis and employ pathway and gene expression analyses. Four-hundred forty-three CpGs (320 genes) are significantly associated with maternal plasma folate levels during pregnancy (false discovery rate 5%); 48 are significant after Bonferroni correction.

Most genes are not known for folate biology,including APC2GRM8SLC16A12OPCMLPRPHLHX1KLK4and PRSS21. Some relate to birth defects other than neural tube defects, neurological functions or varied aspects of embryonic development.

These findings may inform how maternal folate impacts the developing epigenome and health outcomes in offspring.