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Clin Epigenetics. 2018 Mar 13;10:34. doi: 10.1186/s13148-018-0468-1. eCollection 2018.

No evidence for association of MTHFR 677C>T and 1298A>C variants with placental DNA methylation.

Author information

1
1BC Children's Hospital Research Institute, 950 W 28th Ave, Vancouver, BC V5Z 4H4 Canada.
2
2Department of Medical Genetics, University of British Columbia, 4500 Oak St, Vancouver, BC V6H 3N1 Canada.
3
3Epigenetics Programme, Babraham Institute, Cambridge, CB22 3AT UK.
4
4Centre for Trophoblast Research, University of Cambridge, Cambridge, CB2 3EG UK.
5
5Child and Family Research Institute, Room 2082, 950 W 28th Avenue, Vancouver, BC V5Z 4H4 Canada.

Abstract

Background:

5,10-Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in one-carbon metabolism that ensures the availability of methyl groups for methylation reactions. Two single-nucleotide polymorphisms (SNPs) in the MTHFR gene, 677C>T and 1298A>C, result in a thermolabile enzyme with reduced function. These variants, in both the maternal and/or fetal genes, have been associated with pregnancy complications including miscarriage, neural tube defects (NTDs), and preeclampsia (PE), perhaps due to altered capacity for DNA methylation (DNAm). In this study, we assessed the association between MTHFR 677TT and 1298CC genotypes and risk of NTDs, PE, or normotensive intrauterine growth restriction (nIUGR). Additionally, we assessed whether these high-risk genotypes are associated with altered DNAm in the placenta.

Results:

In 303 placentas screened for this study, we observed no significant association between the occurrence of NTDs (N = 55), PE (early-onset: N = 28, late-onset: N = 20), or nIUGR (N = 21) and placental (fetal) MTHFR 677TT or 1298CC genotypes compared to healthy pregnancies (N = 179), though a trend of increased 677TT genotype in PE/IUGR together was observed (OR 2.53, p = 0.048). DNAm was profiled in 10 high-risk 677 (677TT + 1298AA), 10 high-risk 1298 (677CC + 1298CC), and 10 reference (677CC + 1298AA) genotype placentas. Linear modeling identified no significantly differentially methylated sites between high-risk 677 or 1298 and reference placentas at a false discovery rate < 0.05 and Δβ ≥ 0.05 using the Illumina Infinium HumanMethylation450 BeadChip. Using a differentially methylated region analysis or separating cytosine-guanine dinucleotides (CpGs) by CpG density to reduce multiple comparisons also did not identify differential methylation. Additionally, there was no consistent evidence for altered methylation of repetitive DNA between high-risk and reference placentas.

Conclusions:

We conclude that large-scale, genome-wide disruption in DNAm does not occur in placentas with the high-risk MTHFR 677TT or 1298CC genotypes. Furthermore, there was no evidence for an association of the 1298CC genotype and only a tendency to higher 677TT in pregnancy complications of PE/IUGR. This may be due to small sample sizes or folate repletion in our Canadian population attenuating effects of the high-risk MTHFR variants. However, given our results and the conflicting results in the literature, investigations into alternative mechanisms that may explain the link between MTHFR variants and pregnancy complications, or in populations at risk of folate deficiencies, are warranted.

KEYWORDS:

450k array; DNA methylation; IUGR; MTHFR; Neural tube defects; One-carbon metabolism; Placenta; Preeclampsia

PMID:
29564022
PMCID:
PMC5851070
DOI:
10.1186/s13148-018-0468-1
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

Ethics approval for this study was obtained from the University of British Columbia/Children’s Hospital and Women’s Health Centre of British Columbia Research Ethics Board (H04-70488, H10-01028). For all control, PE, nIUGR, and some NTD cases (N = 261), mothers provided informed written consent to participate prior to delivery or termination of pregnancy. For certain NTD cases obtained retrospectively from pathological autopsy specimens (N = 42), biospecimens were de-identified and unlinked to clinical data. For all cases, only non-identifiable information is presented in this publication.Not applicable.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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