Abstract
BackgroundThe incidence of neural tube defects (NTDs) declined by about 40 % in Canada with the introduction of a national folic acid (FA) fortification program. Despite the fact that few Canadians currently exhibit folate deficiency, NTDs are still the second most common congenital abnormality. FA fortification may have aided in reducing the incidence of NTDs by overcoming abnormal one carbon metabolism cycling, the process which provides one carbon units for methylation of DNA. We considered that NTDs persisting in a folate-replete population may also occur in the context of FA-independent compromised one carbon metabolism, and that this might manifest as abnormal DNA methylation (DNAm). Second trimester human placental chorionic villi, kidney, spinal cord, brain, and muscle were collected from 19 control, 22 spina bifida, and 15 anencephalic fetuses in British Columbia, Canada. DNA was extracted, assessed for methylenetetrahydrofolate reductase (MTHFR) genotype and for genome-wide DNAm using repetitive elements, in addition to the Illumina Infinium HumanMethylation450 (450k) array.ResultsNo difference in repetitive element DNAm was noted between NTD status groups. Using a false discovery rate <0.05 and average group difference in DNAm ≥0.05, differentially methylated array sites were identified only in (1) the comparison of anencephaly to controls in chorionic villi (n = 4 sites) and (2) the comparison of spina bifida to controls in kidney (n = 3342 sites).ConclusionsWe suggest that the distinctive DNAm of spina bifida kidneys may be consequent to the neural tube defect or reflective of a common etiology for abnormal neural tube and renal development. Though there were some small shifts in DNAm in the other tested tissues, our data do not support the long-standing hypothesis of generalized altered genome-wide DNAm in NTDs. This finding may be related to the fact that most Canadians are not folate deficient, but it importantly opens the field to the investigation of other epigenetic and non-epigenetic mechanisms in the etiology of NTDs.Electronic supplementary materialThe online version of this article (doi:10.1186/s13072-016-0054-8) contains supplementary material, which is available to authorized users.
Highlights
The incidence of neural tube defects (NTDs) declined by about 40 % in Canada with the introduction of a national folic acid (FA) fortification program
These include genes for which mutations in mice lead to the development of NTDs, in addition to loci involved in one-carbon metabolism
We profiled DNA methylation (DNAm) in five fetal tissues ascertained from cases of NTDs in British Columbia, a folate replete population, to test whether abnormal DNAm was a feature of NTDs that develop despite FA fortification
Summary
The incidence of neural tube defects (NTDs) declined by about 40 % in Canada with the introduction of a national folic acid (FA) fortification program. A hypothesis of altered capacity for DNA methylation (DNAm) has been proposed as the mechanism underlying FA prevention of NTDs [8] The basis of this hypothesis was the observation of increased incidence of NTDs in association with maternal and fetal SNPs in methylenetetrahydrofolate reductase (MTHFR) [9], the enzyme at the intersection of the DNA and methylation cycles. These MTHFR variants result in reduced enzymatic activity [10, 11] which is expected to shift OCM toward the DNA cycle, restricting methylation capacity and leading to abnormal patterns of DNAm [8, 12]. Despite research and policy changes, NTDs remain the second most common congenital abnormality in many parts of the world [22], and the etiology of persisting cases is unknown
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