The impact of pre‐pregnancy folic acid intake on placental DNA methylation in a fortified cohort

Folate plays an important role in the modulation of one‐carbon metabolism and DNA methylation through a complex biosynthesis pathway. Folate deficiency during pregnancy has been associated with an increased risk for birth defects. This study investigates the extent to which the availability of folate and S‐Adenosylmethionine (SAM) affects placental DNA methylation. We hypothesized that maintaining sufficient levels of folate and SAM is particularly important in individuals carrying the MTHFR C677T polymorphism. Maternal‐ and cord blood was analyzed to genotype the MTHFR rs1801133 SNP. Red blood cell (RBC) folate, vitamin B12, SAM, and S‐Adenosylhomocysteine (SAH) were analyzed in cord blood. Epigenome‐wide methylation analyses were performed on 90 placenta tissue samples isolated from the fetal side of the placenta; 45 originating from mother‐infant dyads homozygous for the MTHFR C677T variant and 45 originating from mother‐infant dyads with the homozygous wild type MTHFR677 genotype. Verification of the results was performed using pyrosequencing assays. Genome‐wide placental DNA methylation patterns were relatively stable and not significantly affected by levels of one‐carbon metabolites. MTHFR genotype was associated with DNA methylation of several loci, including a locus in the MTHFR region. RBC folate and particularly the SAM:SAH ratio did affect overall CpG DNA methylation in some CpG regions when the loci were split according to their CpG island relation. This was most evident in participants carrying the MTHFR C677T variant suggesting a stronger influence of the biosynthesis pathway on the overall placental DNA methylation in MTHFR TT individuals than in MTHFR CC individuals.