Epigenetic Profiles in Children with a Neural Tube Defect; a Case-control Study in Two Populations

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2013 Nov 14

PMID 24223810

Citations 6

Authors

Lisette Stolk

Marieke I Bouwland-Both

Nina H van Mil

Nina H van Mill

Michael M P J Verbiest

Paul H C Eilers

Huiping Zhu

Lucina Suarez

Andre G Uitterlinden

Regine P M Steegers-Theunissen

Affiliations

Soon will be listed here.

Abstract

Folate deficiency is implicated in the causation of neural tube defects (NTDs). The preventive effect of periconceptional folic acid supplement use is partially explained by the treatment of a deranged folate-dependent one carbon metabolism, which provides methyl groups for DNA-methylation as an epigenetic mechanism. Here, we hypothesize that variations in DNA-methylation of genes implicated in the development of NTDs and embryonic growth are part of the underlying mechanism. In 48 children with a neural tube defect and 62 controls from a Dutch case-control study and 34 children with a neural tube defect and 78 controls from a Texan case-control study, we measured the DNA-methylation levels of imprinted candidate genes (IGF2-DMR, H19, KCNQ1OT1) and non-imprinted genes (the LEKR/CCNL gene region associated with birth weight, and MTHFR and VANGL1 associated with NTD). We used the MassARRAY EpiTYPER assay from Sequenom for the assessment of DNA-methylation. Linear mixed model analysis was used to estimate associations between DNA-methylation levels of the genes and a neural tube defect. In the Dutch study group, but not in the Texan study group we found a significant association between the risk of having an NTD and DNA methylation levels of MTHFR (absolute decrease in methylation of -0.33% in cases, P-value = 0.001), and LEKR/CCNL (absolute increase in methylation: 1.36% in cases, P-value = 0.048), and a borderline significant association for VANGL (absolute increase in methylation: 0.17% in cases, P-value = 0.063). Only the association between MTHFR and NTD-risk remained significant after multiple testing correction. The associations in the Dutch study were not replicated in the Texan study. We conclude that the associations between NTDs and the methylation of the MTHFR gene, and maybe VANGL and LEKKR/CNNL, are in line with previous studies showing polymorphisms in the same genes in association with NTDs and embryonic development, respectively.

Citing Articles

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Folic acid intervention during pregnancy alters DNA methylation, affecting neural target genes through two distinct mechanisms.

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Different epigenetic alterations are associated with abnormal IGF2/Igf2 upregulation in neural tube defects.

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