Abstract
BackgroundDNA methylation is an epigenetic process for modifying transcription factors in various genes. Methylenetetrahydrofolate reductase (MTHFR) stimulates synthesis of methyl radical in the homocysteine cycle and delivers methyl groups needed in DNA methylation. Furthermore, numerous studies have linked gene polymorphisms of this enzyme with a larger risk of recurrent pregnancy loss (RPL), yet scarce information is available concerning the association between epigenetic deviations in this gene and RPL. Hypermethylation at precise DNA sequences can function as biomarkers for a diversity of diseases. We aimed by this study to evaluate the methylation status of the promoter region of MTHFR gene in women with RPL compared to healthy fertile women. It is a case–control study. Hundred RPL patients and hundred healthy fertile women with no history of RPL as controls were recruited. MTHFR C677T was assessed by polymerase chain reaction-restriction fragment length polymorphism (RFLP). Quantitative evaluation of DNA methylation was performed by high-resolution melt analysis by real-time PCR. ResultsThe median of percentage of MTHFR promoter methylation in RPL cases was 6.45 [0.74–100] vs. controls was 4.50 [0.60–91.7], P value < 0.001. In the case group, 57 hypermethylated and 43 normo-methylated among RPL patients vs. 40 hypermethylated and 60 normo-methylated among controls, P< 0.005. Frequency of T allele in C677T MTHFR gene among RPL patients was 29% vs. 23% among the control group; C allele vs. T allele: odds ratio (OR) = 1.367 (95% confidence interval (CI) 0.725–2.581). ConclusionFindings suggested a significant association between hypermethylation of the MTHFR promoter region in RPL patients compared to healthy fertile women.
Highlights
DNA methylation is an epigenetic process for modifying transcription factors in various genes
Analysis for C677T polymorphism was done after methylation quantification to assess if there is a direct correlation between the polymorphism and methylation status in coding region of Methylenetetrahydrofolate reductase (MTHFR) in recurrent pregnancy loss (RPL) patients
The results showed that RPL cases were hypermethylated for MTHFR gene in comparison to healthy fertile female in the control group with a statistical significance p= 0.002
Summary
DNA methylation is an epigenetic process for modifying transcription factors in various genes. We aimed by this study to evaluate the methylation status of the promoter region of MTHFR gene in women with RPL compared to healthy fertile women. RPL is defined as more than two to three consecutive pregnancy losses earlier to the 20th week of gestation [1]. Still DNA methylation is the utmost commonly assessed epigenetic modification in context of RPL. It represents the methylation of cytosines at CpG (cytosine–phosphate–guanine) dinucleotide. Pliushch et al [9] stated that epimutations that lead to unsuitable methylation and expression patterns of genes may add to increased incidence of pregnancy failures
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