Periconceptional maternal folic acid use of 400 microg 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 microg 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.


RESULTS
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.
Steegers-Theunissen
Régine P
RP
Obstetrics and Gynecology/Division of Obstetrics and Prenatal Medicine, Erasmus MC, University Medical Center, Rotterdam, The Netherlands. r.steegers@erasmusmc.nl
Obermann-Borst
Sylvia A
SA
Kremer
Dennis
D
Lindemans
Jan
J
Siebel
Cissy
C
Steegers
Eric A
EA
Slagboom
P Eline
PE
Heijmans
Bastiaan T
BT
D000328:Adult; D001724:Birth Weight; D018899:CpG Islands; D003430:Cross-Sectional Studies; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D005492:Folic Acid / Q000008:administration & dosage / Q000627:therapeutic use*; D005786:Gene Expression Regulation; D006801:Humans; D007223:Infant; D007335:Insulin-Like Growth Factor II / Q000096:biosynthesis* / Q000235:genetics*; D008297:Male; D016742:Preconception Care; D011247:Pregnancy; D012435:S-Adenosylhomocysteine / Q000097:blood; D012436:S-Adenosylmethionine / Q000097:blood
D007335:Insulin-Like Growth Factor II; D012436:S-Adenosylmethionine; D005492:Folic Acid; D012435:S-Adenosylhomocysteine