Folate in pregnancy and imprinted gene and repeat element methylation in the offspring

Abstract

Background: Epigenetic regulation of imprinted genes and transposable elements has been implicated in human disease and may be affected by maternal diet. Objective: The objective was to determine the effect on offspring epigenetic status of nutritional and genetic factors that influence folate exposure in pregnancy. Design: We measured folate intake from diet, the use of folic acid supplements and the period of consumption, maternal and cord red blood cell (RBC) folate, and genotypes for 5 methylation cycle enzymes in a prospective cohort study of pregnancies in the United Kingdom between 2000 and 2006. We related these to offspring methylation status within 3 maternally methylated imprinted genes: paternally expressed gene 3 ( PEG3 ), insulin-like growth factor 2 (IGF2), and small nuclear ribonucleoprotein polypeptide N, and the long interspersed nuclear element 1 (LINE-1) in genomic DNA extracted from whole blood in 913 pregnancies. Results: Supplement use after 12 wk of gestation was associated with a higher level of methylation in IGF2 (+0.7%; 95% CI: 0.02, 1.4; P = 0.044) and reduced methylation in both PEG3 (20.5%; 95% CI: 20.9, 20.1; P = 0.018) and LINE-1 (20.3%; 95% CI: 20.6, 20.04; P = 0.029). The same pattern was observed in relation to RBC folate in the cord blood at birth: IGF2 (P = 0.038), PEG3 (P < 0.001), and LINE-1 (P < 0.001). LINE-1 methylation was related to maternal RBC folate (P = 0.001) at 19 wk. No effect of supplement use up to 12 wk (current recommendation) was found. Conclusions: Folic acid use after 12 wk of gestation influences offspring repeat element and imprinted gene methylation. We need to understand the consequences of these epigenetic effects. © 2013 American Society for Nutrition.