ABSTRACT
Background: According to various epidemiological studies, the aetiology of recurrent miscarriages (RMs) is multifactorial. The goal of this study is to learn more about the link between genetic polymorphisms and RM. Aim: To evaluate the association of 5-Methytetrahydrofolate-Homocysteine Methyltransferase (MTR) A2756G, 5-Methytetrahydrofolate-Homocysteine Methyltransferase Reductase (MTRR) A66G and cystathionine beta-synthase (CBS) 844INS68 genetic polymorphisms with RM and also to understand the combined effect of the selected genotypes. Study Setting and Design: This was a hospital-based, case-control, observational study. Materials and Methods: A total of 516 participants were recruited in the present study, of which 200 RM cases and 258 controls were included in the present study. Fasting blood sample (~5ml) was drawn from all the participants and were screened for genetic polymorphisms of MTR A2756G, MTRR A66G and CBS 844INS68. Statistical Analysis: The frequency, odd's ratio and Hardy-Weinberg equilibrium were evaluated. SPSS (version 21.0) was used for the data analysis. Results: MTR A2756G genetic polymorphism was not associated with the risk of RM. The ancestral allele of MTRR A66G and the mutant allele of CBS 844INS68 was causing an increased risk of more than two folds for RM. CBS 844INS68 in combination with MTR A2756G was found to pose an increased risk of more than two folds for RM. Conclusion: Genetic polymorphisms particularly MTRR A66G and CBS 844INS68 seems to be elevating the risk and hence making women susceptible for RM.
ABSTRACT
AIM: The purpose of the present study is to evaluate and understand the association of global and MTHFR gene specific methylation in preeclampsia and recurrent miscarriages in light of MTHFR C677T polymorphism. METHODS: The subjects comprised of recurrent miscarriage cases, their gestation matched controls, preeclampsia cases and matched controls. A set of women at full term were also recruited. Fasting blood sample (~5â¯ml) was drawn from all the participants followed by DNA extraction, global DNA methylation and MTHFR gene specific methylation. MTHFR C677T polymorphism was analysed by PCR followed by RFLP. RESULTS HIGHER: Global DNA methylation at maternal front (pâ¯=â¯0.04) and hypomethylation of MTHFR gene at fetal front (pâ¯=â¯0.001) might be a characteristic of preeclampsia. Recurrent miscarriage cases were having significantly (pâ¯=â¯0.002) hyper MTHFR gene specific methylation as compared to controls. Women carrying CT genotype were found to be having significantly (pâ¯=â¯0.001) higher global DNA methylation in PE cases and MTHFR gene specific methylation (pâ¯=â¯0.005) in RM cases. Intergenerational analysis revealed similar patterns of global DNA methylation and MTHFR gene specific methylation among both PE and RM cases at maternal and fetal fronts. CONCLUSION: The study highlights the importance of global DNA methylation in Preeclampsia and MTHFR gene specific methylation in recurrent miscarriages. MTHFR C677T gene polymorphism in association with global and gene specific methylation seem to play a pivotal role in PE and RM respectively.
Subject(s)
Abortion, Habitual/genetics , DNA Methylation , Methylenetetrahydrofolate Reductase (NADPH2)/genetics , Pre-Eclampsia/genetics , Adult , Case-Control Studies , Female , Genetic Association Studies , Genetic Predisposition to Disease , Homocystinuria/complications , Homocystinuria/genetics , Humans , India , Methylenetetrahydrofolate Reductase (NADPH2)/deficiency , Muscle Spasticity/complications , Muscle Spasticity/genetics , Polymorphism, Restriction Fragment Length , Polymorphism, Single Nucleotide , Pre-Eclampsia/diagnosis , Pregnancy , Pregnancy Trimester, Second/genetics , Pregnancy Trimester, Third/genetics , Psychotic Disorders/complications , Psychotic Disorders/geneticsABSTRACT
AIM: This study aimed to understand the association of gene-specific methylation of the promoter region of methylenetetrahydrofolate reductase (MTHFR) in the causation of recurrent miscarriages (RMs) both independently and also in light of MTHFR C677T polymorphism, hyperhomocysteinemia, folate, and Vitamin B12 deficiency. SETTINGS AND DESIGN: This was a hospital-based, case-control, observational study. METHODS: The proposed study included a total of 85 RM cases and 121 nonpregnant controls. Biochemical (homocysteine, folate, and Vitamin B12) investigations, MTHFR polymorphism (C677T), and MTHFR allele-specific methylation were done on all the samples. RESULTS: Methylation-specific polymerase chain reaction of MTHFR gene revealed that methylated allele (single dose) was found to pose a significant 3.6-fold increased risk for RM. The degree of risk of methylated allele for RM was found to be aggravated from the normal genotype CC (2.8 folds) to CT (7.5 folds) individuals. Vitamin B12 deficiency and folate repletion were found to be posing an increased risk in association with methylated allele for recurrent miscarriages as compared to the respective controls. CONCLUSION: Recurrent miscarriage cases were found to be hypermethylated with respect to MTHFR gene-specific methylation as compared to the controls. High prevalence of folate repletion causing imbalance between folate and Vitamin 12 levels may lead to hypermethylation among recurrent miscarriage cases. The present study highlights the significance of the epigenetic mechanisms in the causation of the recurrent miscarriages.
