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.
Highlights
Neural tube defects (NTDs) are congenital malformations accompanied with low birth weight, which result from a failure of the neural tube to close during the fourth week of embryogenesis
In two cohorts of NTD cases and controls, we studied associations between DNA-methylation levels in fetuses and very young children using a candidate gene approach of imprinted candidate genes (IGF2, H19, and KCNQ1OT1) and nonimprinted LEKR/CCNL gene region involved in embryonic development and MTHFR, and VANGL1 that are associated with NTDs
The Dutch cases and controls were investigated at the standardised age of approximately 15 months, while the Texan study groups were investigated after pregnancy termination or birth at the time of the Guthrie test
Summary
Neural tube defects (NTDs) are congenital malformations accompanied with low birth weight, which result from a failure of the neural tube to close during the fourth week of embryogenesis. A maternal folate shortage during the sensitive period of neural tube development contributes to the development of NTD, and the occurrence of the disease can be reduced by periconceptional maternal folic acid supplement use [2]. DNA-methylation of genes is rather stable throughout life, except for example in the periconception period. It is an important mechanism in epigenetic programming of tissues, organ development and functioning. Maternal vitamin B12 deficiency has been associated with an increased risk for NTD [6,7,8,9,10], linking maternal 1-C metabolism to closure of the neural tube in the developing child
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