Epigenetic Modification in Methylene Tetrahydrofolate Reductase (MTHFR) Gene of Women with Pre-eclampsia.

BACKGROUND: Genetic and epigenetic factors play significant roles in the aetio-pathogenesis of pre-eclampsia (PE). The effects may vary across racial and geographical boundaries. The role of epigenetic modification in pre-eclampsia was studied among African populations in Lagos, Nigeria. AIM AND OBJECTIVES: This study aimed to determine the pattern of Methylene tetrahydrofolate reductase gene (MTHFR) CpG island methylation in pre-eclampsia, and evaluate associated covariates. METHODOLOGY: This study was an observational, cross-sectional, study conducted at the Lagos University Teaching Hospital and the Lagos State Island Maternity Hospital. A total of 400 pregnant women consisting of 200 pregnant women diagnosed with pre-eclampsia (study group) and 200 pregnant normotensive and apparently healthy women (control group) were recruited for the study. Demographic and clinical histories were obtained through questionnaires. The DNA Methylation status of the CpG Island in promoter region of the MTHFR gene was assessed using bisulphite conversion and methylation specific PCR method. The biochemical parameters measured in the study were: red cell folate, vitamin B12, plasma homocysteine (Hcy) and methylene tetrahydrofolate reductase enzyme level. RESULTS: Homozygous MTHFR CpG island hypomethylation pattern was significantly associated with pre-eclampsia (χ 2 = 22.96; p = 0.000), Mean values of plasma homocysteine in PE women with homozygous hypomethylation (26.1 ± 9.1 umol/L) were significantly higher than (20.1 ± 4.2 umol/L) observed in PE subjects with homozygous hypermethylation (p = 0.008). Homozygous CpG island hypomethylated pattern of the MTHFR promoter region, was associated with the lowest median MTHFR enzyme level (72.8 ± 39.8 pmol/L) compared with heterozygous methylated pattern (91.3 ± 60.9 pmol/L; p = 0.047) and homozygous methylated pattern (82.3 ± 31.0 pmol/L; 0.047). Red cell folate and Vitamin B12 levels were not significantly associated with CpG island methylation status. CONCLUSION: Epigenetic modification plays significant role in the pathogenesis of pre-eclampsia.

Methylene tetrahydrofolate reductase and methionine synthase gene polymorphisms as genetic determinants of pre-eclampsia.

BACKGROUND: Pre-eclampsia (PE) is a leading cause of maternal and neonatal mortality in Africa; and has been associated with the interplay of genetic, metabolic and environmental factors. Polymorphisms of methylene tetrahydrofolate reductase (MTHFR) and methionine synthase (MTR) folate cycle genes, have been controversially associated with pre-eclampsia in studies from different human populations. OBJECTIVES: To determine the distribution of MTHFR C677T and MTR A2756G polymorphisms in a Nigerian population and evaluate possible associations with the occurrence of pre-eclampsia and homocysteine metabolic derangement. MATERIALS AND METHODS: This study was a hospital based study carried out in Lagos, South-western Nigeria. Two hundred pregnant women clinically diagnosed with pre-eclampsia (study group) and 200 apparently healthy non-pre-eclamptic pregnant women (control group) were recruited for the study after written informed consent. Pre-eclampsia was diagnosed based on the International Society for the Study of Hypertension in Pregnancy re-classification of 2013. MTHFR C677T and MTR A2756G polymorphisms were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Statistical analyzes were performed using SPSS version 23. Hardy-Weinberg distribution were tested with χ2 test. Logistic regression model was used to evaluate the relationship of variables with pre-eclampsia. A value of p < 0.05 was considered statistically significant. RESULTS: MTHFR genotype frequencies of CC, CT and TT were 59.8%; 31.2% and 9.0% in study group and 76.6%; 22.3% and 1.0% in the control group respectively. MTR A2756G genotype frequencies of AA, AG and GG genotypes were 71.9%; 20.1% and 8.0% for the study group and 81.5%; 16.4% and 2.1% for the control group. Occurrence of pre-eclampsia was significantly associated with presence of T allele of MTHFR (OR = 1.855; p < 0.05) and G allele of MTR genes (OR = 1.269; p < 0.05), Homozygosity of TG haplotype significantly increased the occurrence of pre-eclampsia among Nigerian women (OR = 2.252; p < 0.05). Population attributable risk fraction percent for the T and G alleles were 16.4% and 11.5% respectively. Mean plasma Hcy level was not, however, significantly affected by MTHFR/MTR haplotypes (F = 1.54; p = 0.157). CONCLUSION: MTHFR C677T and MTR A2756G polymorphisms were associated with pre-eclampsia in a population of pregnant women in Lagos, Nigeria.

Methylenetetrahydrofolate Reductase Enzyme Level and Antioxidant Activity in Women with Gestational Hypertension and Pre-eclampsia in Lagos, Nigeria.

BACKGROUND: Deficiencies of enzymes in the folate cycle may lead to the generation of homocysteine, a toxic metabolic intermediate with pro-oxidant effect and ability to induce oxidant stress and lipid peroxidation as part of the pathophysiological process in gestational hypertension (GH) and pre-eclampsia (PE). AIM: The aim of this study is to assess the reliability of plasma homocysteine (hcy) 5, 10 methylenetetrahydrofolate reductase (MTHFR) enzyme and oxidative stress parameters as indicators of aetio-pathogenesis and severity of gestational hypertension and pre-eclampsia. SUBJECTS AND METHODS: This was a comparative cross-sectional study conducted over 6 months. Two hundred pregnant women were recruited from two sites. They were divided into gestation hypertension (n = 40), pre-eclampsia (n = 60) and control groups (n = 100). Parameters evaluated for statistical analysis were MTHFR enzyme level, plasma homocysteine and malondialdehyde (MDA) levels, with glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) activities. RESULTS: Mean plasma hcy level and MDA were significantly higher in pre-eclampsia and gestational hypertension when compared to control group (p < 0.05). However, MTHFR enzyme level, GSH, SOD and CAT were significantly higher in normotensive females when compared to PE and GH subgroups (p < 0.05). Pre-eclampsia was significantly associated with an increased risk of lipid peroxidation (OR = 4.923; p = 0.007). CONCLUSION: Pre-eclampsia and gestational hypertension are associated with marked homocysteine metabolic derangement and increased lipid peroxidation induced by oxidative stress and reduced MTHFR enzyme activity which may be the significant risk factors in the aetio-pathogenesis of GH and PE.