Polymorphisms of the methylenetetrahydrofolate reductase gene (C677T and A1298C) in the placenta of pregnancies complicated with preeclampsia

Chedraui, Peter; Andrade, Mariela E.; Salazar-Pousada, Danny; Escobar, Gustavo S.; Hidalgo, Luis; Ramírez, Cecibel; Spaanderman, Marc E. A.; Kramer, Boris W.; Gavilanes, Antonio W. D.

doi:10.3109/09513590.2015.1031104

Cited by 15 publications

(22 citation statements)

References 22 publications

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“…In our study population, we found no significant association of NTDs, EOPE, LOPE, or nIUGR with high-risk 677TT or 1298CC placental genotypes, although there was a tendency to increased MTHFR 677TT in pregnancies affected by PE or IUGR as a whole (OR 2.53, p = 0.048). This trend is consistent with the literature noting an increased risk of PE in association with the 677T allele in both the maternal blood and the placenta [ 27 , 29 ]. In a recent meta-analysis of 52 different studies, with a combined total of 7398 PE cases and 11,230 controls, Wu et al identified a significantly increased risk of PE in association with the MTHFR 677T allele [ 28 ].…”

Section: Discussionsupporting

confidence: 93%

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

et al. 2018

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Background5,10-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.ResultsIn 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.ConclusionsWe 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.Electronic supplementary materialThe online version of this article (10.1186/s13148-018-0468-1) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 93%

“…The 677T allele and 677TT genotype in mothers have been associated with preeclampsia (PE), a maternal hypertensive disorder in pregnancy [ 26 – 28 ]. Associations between fetal-placental MTHFR 677TT genotypes have been identified [ 29 ], though these are not as well studied as the maternal variants.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2018

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“…Previous studies have demonstrated that the enzyme activity of MTHFR 1298A/A and 1298A/C gene was normal and the enzyme activity of MTHFR 1298C/C gene was reduced, further decline of enzyme activity influenced the level of folic acid and HCY concentration, ultimately increase the risk of APO (Chedraui et al, ). We found no significant difference in the frequency of MTHFR 1298C/C genotype between patients with APO and healthy controls in Yunnan.…”

Section: Discussionmentioning

confidence: 99%

“…MTHFR 677C>T and 1298A>C locus have long been investigated (Chedraui et al, 2015;Li, Chen, Guo, & Qiang, 2015;Stangler et al, 2013). A number of studies have shown that polymorphism of MTHFR 677C>T is one of the main causes of APO (Liu, Yan, & Yang, 2015;Sun, Wang, & Feng, 2017;Wang et al., 2010).…”

Section: Introductionmentioning

confidence: 99%

Polymorphism of MTHFR 1298A>C in relation to adverse pregnancy outcomes in Chinese populations

Hui

Rao

Wang

et al. 2019

Molec Gen & Gen Med

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Background Adverse pregnancy outcomes (APOs) are involved in a series of abnormal pregnancies like embryo growth arrest, spontaneous abortion, premature birth, stillbirth, fetal malformation, birth defects and other pathological pregnancy, and childbirth complications. Polymorphism of methylenetetrahydrofolate reductase gene ( MTHFR , 607093) is one of the main genetic causes of APO. However, there is still debate on whether MTHFR 1298A>C, rs1801131, polymorphism is related to APO. For the lack of extensive research in the Chinese population at present, the study aim to investigate the relationship between MTHFR 1298A>C polymorphism with APO through a large number of data. Methods A total of 241 samples from patients with APO and 117 healthy controls in Yunnan province were used for MTHFR gene polymorphism analysis, with double fluorescence quantitative polymerase chain reaction (PCR). In consideration of the low frequency of MTHFR 1298C/C genotype, which might affect the statistic results, further datasets of MTHFR 1298A>C polymorphism were collected from literature and analyzed. Results No statistical difference was detected in the frequency of MTHFR 1298A>C polymorphism between two groups in Yunnan. Our data showed that the frequency of MTHFR 1298A/A genotype had the decreasing tendency among Chinese population from northern to southern, as well as eastern to western of China. The frequency of MTHFR 1298A/C and 1298C/C genotypes had the adverse tendency. The frequency of MTHFR 1298C/C genotype was significantly different between two groups in Chinese populations. The significant difference was also observed in the frequency of MTHFR 1298C/C polymorphism between two groups from central China and southern China. Conclusion In summary, our data showed that MTHFR 1298C/C genotype was one of the important genetic factors of APO in China.

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“…Therefore, various studies have evaluated the effects of maternal MTHFR genetic variations and PE. However, the published reports on the association between genetic and epigenetic variations in placental MTHFR are sparse in number …”

Section: Discussionmentioning

confidence: 99%

The association of the placental MTHFR 3′‐UTR polymorphisms, promoter methylation, and MTHFR expression with preeclampsia

Mohammadpour‐Gharehbagh

Teimoori

Narooei‐Nejad³

et al. 2017

J of Cellular Biochemistry

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Preeclampsia (PE) is a pregnancy specific complication arises in presence of the placenta and disappears immediately after delivery. Therefore, the aim of the present study was to investigate the possible effects of the placental 3'-UTR rs1537514C>G and rs4846049C>A polymorphisms and DNA methylation of the MTHFR gene on the MTHFR mRNA expression. The placenta of 74 PE pregnant women and 75 normotensive pregnant women were collected after delivery. The methylation status of the MTHFR promoter was assessed with Methylation Specific PCR (MSP). The rs1537514C>G and rs4846049C>A polymorphisms were genotyped using PCR-RFLP method. The mRNA expression levels were measured by Quantitative Real Time PCR. The results showed the lower MTHFR mRNA expression in the placenta of PE women. There was an association between hypermethylation and lower MTHFR mRNA expression in PE women and entire women but not normotensive pregnant women. The frequency of MTHFR rs1537514CG genotype was significantly lower in PE women; however, there was no association between MTHFR rs4846049C>A polymorphism and PE. The combination effects of MTHFR CG/AC genotypes and G-A haplotype of MTHFR rs1537514/rs4846049 polymorphisms were associated with lower risk of PE. The MTHFR rs1537514G (4869G) allele was associated with higher MTHFR mRNA expression in both groups. However, there was no relation between MTHFR rs4846049C>A polymorphism and MTHFR mRNA expression. Our findings showed lower MTHFR mRNA expression in PE women. The MTHFR rs1537514C>G polymorphism was associated with lower PE risk and MTHFR mRNA expression. Lower expression of MTHFR mRNA was observed in the women with the hypermethylated promoter.

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Polymorphisms of the methylenetetrahydrofolate reductase gene (C677T and A1298C) in the placenta of pregnancies complicated with preeclampsia

Abstract: This study found that the frequency of the TT mutant genotype of the C677T polymorphism was higher in the placenta of pregnancies complicated with preeclampsia. There is a need for further research in this matter.

Cited by 15 publications

References 22 publications

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

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

Polymorphism of MTHFR 1298A>C in relation to adverse pregnancy outcomes in Chinese populations

The association of the placental MTHFR 3′‐UTR polymorphisms, promoter methylation, and MTHFR expression with preeclampsia

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