Editors' ChoiceEpigenetics

Balance of nutrients: Is more better?

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Science Translational Medicine  24 Feb 2016:
Vol. 8, Issue 327, pp. 327ec32
DOI: 10.1126/scitranslmed.aaf3853

When it comes to dietary supplements, many get their (often erroneous) information from health magazines or television doctors. Take folic acid, for example: Fortification programs that enhance folate status in human populations have gained popularity. However, although folic acid supplementation before conception clearly reduces the rate of fetal neural tube defects, higher folic acid intake during pregnancy has been associated with an increased risk of childhood retinoblastoma and early respiratory illness. Further, we have not yet deciphered the underlying mechanisms that specify folic acid intake effects on normal development and disease. Because folate is a major provider of a methyl group in the one-carbon metabolism pathway, epigenetic modifications— specifically, DNA methylation—could be involved. To understand the biological implications of folate status on the developing fetus, Joubert et al. performed a meta-analysis on two independent cohorts (n = 1988) to test associations between maternal plasma folate concentrations during pregnancy and DNA methylation status in newborn cord blood.

After adjusting for known covariates and stringent statistical testing, the authors found that 443 CpG sites were significantly associated with maternal plasma folate levels during pregnancy, and those CpG sites were significantly enriched in genes that function in fundamental developmental and neurodevelopmental pathways. Vitamin B12, a cofactor that works with folate in one-carbon metabolism, did not confound the folate-methylation associations. The authors also tested the confounding effects of vitamin D intake by the mothers, which might reflect supplement use, as well as single-nucleotide polymorphisms (SNPs) in the methylenetetrahydrofolate reductase (MTHFR) gene that influence one-carbon metabolism and correlate with plasma folate concentrations in the mothers. Neither vitamin D intake nor MTHGR genetic variants showed a confounding effect on the relationship between serum folate concentrations during pregnancy and DNA methylation status in newborn cord blood. Although we could not exclude the existence of other confounders, these results suggest that the variations in newborn DNA methylation measured in this study specifically correlated with maternal plasma folate concentrations. In addition, the authors found that ~10% of the CpGs associated with maternal plasma folate levels during pregnancy were significantly associated with altered expression of nearby genes.

Although the authors identified a large number of genes in cord blood that have functional relevance to various developmental pathways—including genes not previously implicated in biological response to folate—most folate intake−related health outcomes involve the nervous system. Thus, further functional studies are needed to delineate the biological functions of these genes.

B. R. Joubert et al., Maternal plasma folate impacts differential DNA methylation in an epigenome-wide meta-analysis of newborns. Nat. Commun. 10.1038/ncomms10577 (2016). [Full Text]

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