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Epigenetic profiles in children with a neural tube defect; a case-control study in two populations.

Stolk L, Bouwland-Both MI, van Mil NH, van Mill NH, Verbiest MM, Eilers PH, Zhu H, Suarez L, Uitterlinden AG, Steegers-Theunissen RP - PLoS ONE (2013)

Bottom Line: 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.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).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.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.

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.

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Related in: MedlinePlus

Methylation levels per locus stratified by study and case-control status.Box and whisker plots of methylation values (y-axis) of all individuals are shown for each CpG unit (x-axis) for NTD case and control children separately.
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pone-0078462-g001: Methylation levels per locus stratified by study and case-control status.Box and whisker plots of methylation values (y-axis) of all individuals are shown for each CpG unit (x-axis) for NTD case and control children separately.

Mentions: The mean absolute DNA-methylation in the child according to case-control status is shown in Table 2 and Figure 1. The mean methylation presented in Figure 1 is stratified by CpG unit, study and case-control status. Effects and P-values in Table 2 are corrected for CpG, bisulfite treatment plate, maternal education (Dutch and Texan study samples) and age of the child (in the Dutch study only). In the Dutch study, the absolute methylation of MTHFR was 0.33% lower in case children compared to controls (P-value = 0.001). Methylation of VANGL1 was 0.17% (P-value = 0.063) higher and of LEKR/CCNL 1.36% higher (P-value = 0.048) in spina bifida cases as compared to controls. After Benjamini-Hochberg correction for multiple testing only the association with MTHFR remained significant.


Epigenetic profiles in children with a neural tube defect; a case-control study in two populations.

Stolk L, Bouwland-Both MI, van Mil NH, van Mill NH, Verbiest MM, Eilers PH, Zhu H, Suarez L, Uitterlinden AG, Steegers-Theunissen RP - PLoS ONE (2013)

Methylation levels per locus stratified by study and case-control status.Box and whisker plots of methylation values (y-axis) of all individuals are shown for each CpG unit (x-axis) for NTD case and control children separately.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3818348&req=5

pone-0078462-g001: Methylation levels per locus stratified by study and case-control status.Box and whisker plots of methylation values (y-axis) of all individuals are shown for each CpG unit (x-axis) for NTD case and control children separately.
Mentions: The mean absolute DNA-methylation in the child according to case-control status is shown in Table 2 and Figure 1. The mean methylation presented in Figure 1 is stratified by CpG unit, study and case-control status. Effects and P-values in Table 2 are corrected for CpG, bisulfite treatment plate, maternal education (Dutch and Texan study samples) and age of the child (in the Dutch study only). In the Dutch study, the absolute methylation of MTHFR was 0.33% lower in case children compared to controls (P-value = 0.001). Methylation of VANGL1 was 0.17% (P-value = 0.063) higher and of LEKR/CCNL 1.36% higher (P-value = 0.048) in spina bifida cases as compared to controls. After Benjamini-Hochberg correction for multiple testing only the association with MTHFR remained significant.

Bottom Line: 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.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).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.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.

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.

Show MeSH
Related in: MedlinePlus