DNA methylation patterns at the IGF2-H19 locus in offspring and maternal folate intake: a systematic review

Abstract

Folate is a critical methyl-group donor in one-carbon metabolism, and maternal folate exposure during pregnancy has been proposed to influence DNA methylation at imprinted loci involved in fetal growth and developmental programming. This systematic review evaluated the association between maternal folate intake during pregnancy and DNA methylation at the IGF2-H19 locus in offspring tissues. PubMed, Embase, and Epistemonikos were systematically searched for human studies assessing folate or folic acid exposure during pregnancy and DNA methylation at IGF2 and/or H19 in pregnancy-related tissues. Risk of bias was assessed using ROBINS-E for observational studies and the Cochrane RoB 2 tool for randomized controlled trials. Fifteen reports from nine countries met the eligibility criteria, including two randomized controlled trials, two cross-sectional studies, and eleven cohort studies. Findings were heterogeneous according to genomic region, tissue type, and exposure window. Folic acid supplementation showed the most consistent associations at the H19 imprinting control region, where inverse associations with methylation were reported in some cord blood analyses. Results for IGF2 DMR2 varied across studies, whereas associations involving blood folate biomarkers were generally weak and tissue-specific, and dietary folate intake was largely null. No observational study was judged at low overall risk of bias, and both randomized trials were assessed as having some concerns. Overall, maternal folic acid supplementation was associated with modest, region-specific differences in DNA methylation at the IGF2-H19 locus; however, methodological limitations and heterogeneity across studies preclude firm conclusions regarding the biological significance of these associations.