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Overview of the human folate- and vitamin B12-dependent homocysteine metabolism indicating its one-carbon donors and acceptors involved in methyl group biogenesis and DNA synthesis. MTHFR, methylenetetrahydrofolate reductase; MSR, methionine synthase reductase; dUMP, deoxyuridylate; dTMP, deoxythymidylate.
Source publication
The pathogenesis of human spontaneous abortion involves a complex interaction of several genetic and environmental factors. The firm association between increased homocysteine concentration and neural tube defects (NTD) has led to the hypothesis that high concentrations of homocysteine might be embryotoxic and lead to decreased fetal viability. The...
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Several studies suggest that the vitamin B12 (B12) transport system can be used for the cellular delivery of B12-conjugated drugs, also in long-term treatment Whether this strategy will affect the endogenous metabolism of B12 is not known. To study the effect of treatment with excess B12 or an inert derivative, we established a mouse model using im...
Citations
... The epidemiologic study showed that a low serum or plasma folate level was associated with an increased risk of early spontaneous abortion [59][60][61], which could be a level of maternal serum folic acid responsible for spontaneous abortions and development of NTDs. Moreover, maternal serum and erythrocyte folate concentration decreases from the twenty weeks of pregnancy onwards and remain low for a long time after delivery [62][63][64], which could the reason for developing NTDs in the next pregnancy particularly for women with short inter-pregnancy intervals. Hence, periconceptional folic acid supplements can effectively prevent not only the occurrence of NTDs and but also spontaneous abortion during early pregnancy. ...
Introduction
Neural tube defects (NTDs) are severe birth defects caused by nutritional, genetic or environmental factors. Because NTDs continue to have a significant health and economic impact on children and community at large, it is crucial to investigate potential risk factors in order to develop novel approaches to NTDs prevention. Determinants for the development of NTDs differ by country, region as well as within the country. The objective of this study was to identify the determinants of NTDs among newborns delivered in three hospitals found in eastern Ethiopia.
Methods
A hospital-based matched case-control study was conducted among 138 cases and 138 control women who delivered in three teaching hospitals in Eastern Ethiopia in 2021. Data were collected using a structured and pre-tested interviewer-administered questionnaire. Cases were mothers who delivered a neonate with any type of NTDs regardless of gestational age or fetal viability, whereas controls were mothers who delivered an apparently healthy newborn. Chi-square was used to assess the significant difference between the two groups. Conditional logistic regression model was used to generate adjusted odds ratio with its corresponding 95% confidence intervals and compare the two groups.
Results
Anencephaly (51.4%) and spinal bifida (34.1%) were the most frequently observed NTDs. None of study participants took preconception folic acid supplementation. Being a non-formal mothers (AOR = 0.34, 95% CI: 0.12–0.92, P = 0.034), rural residence, (AOR = 3.4, 95% CI: 1.18–9.78, P = 0.023), history of spontaneous abortion (AOR = 2.95, 95% CI: 1.15–7.55, P = 0.023), having severe anemia (AOR = 3.4, 95% CI: 1.17–9.87, P = 0.024), history of fever or cold (AOR = 2.75; 95% CI: 1.05–7.15, P = 0.038), and an exposure to various agro-chemicals (AOR = 3.39, 95% CI: 1.11–10.3, P = 0.032) were independent determinants of NTDs.
Conclusion and Recommendation
In this study, NTDs were associated to several determinant factors in the area, including residential area, history of spontaneous abortion, severe anemia, fever/cold, antibiotic use before or during early pregnancy, and exposure to agrochemicals. Addressing the identified determinants is critical in averting the incidence of NTDs in the study area. Moreover, more research is needed to investigate women’s dietary practices as well as the practice of preconception folic acid supplementation for pregnant women in Ethiopia’s current health care system.
... 11 Review of the evidence on the effects of hyperhomocysteinemia on reproductive outcome show that while there are evidence that maternal hyperhomocysteinemia is a risk factor for recurrent embryo loss and even a first early pregnancy loss, evidence also indicate that genetic polymorphism due to mutation in MTHFR enzyme causing high homocysteine concentration from abnormal folate metabolism increased risk of REPL. 12 Possible mechanisms of the deleterious effects of hyperhomocysteinemia on female reproduction include reduced cell division (e.g., of oogonia or of granulose cells), increased oxidative stress, apoptosis, reduced extra-embryonic vasculogenesis, etc. 13 There has been a growing awareness about reproductive failure with the advent of reproductive techniques and services in Bangladesh recently. The investigation of recurrent pregnancy loss includes laboratory, imaging, invasive and genetic analysis. ...
Background: Recurrent early pregnancy loss is a common but frequently unexplained obstetric problem. As it happens in early weeks of pregnancy, abnormal vasculogenesis and disordered cell multiplication are possible causes. Hyperhomocysteinemia is associated with both these pathological processes. Objective: To assess the association between hyperhomocysteinemia and recurrent pregnancy loss. Materials and Methods: This case-control observational study was conducted in the Department of Gynaecology and Obstetrics of Bangabandhu Sheikh Mujib Medical University, Dhaka during January to December 2015. Sixty patients were divided into two groups: 30 with recurrent pregnancy loss (RPL) as cases and 30 normal healthy mothers as controls. Results: All the subjects were matched in terms of age (p = 0.504). All were within normal BMI range (19.5 to 25 kg/square meter). Subjects in both groups were comparable in height, weight and BMI. 33.3% women of control group were in the low income stratum (monthly income 20000 taka or less) compared to50% of the RPL group. Control group had an equal mix of educational level from below Secondary School to Post-Graduates whereas there were fewer Post Graduate patients (3.3%) in the RPL group compared to control group (23.3%). The frequency of hyperhomocysteinemia (>15 micromoles/L) was significantly higher in cases compared to controls (46.7 vs.16.7%, p= 0.012). Mean homocysteine level was also significantly higher in cases compared to controls (13.67+/-4.80 vs. 9.87+/-4.84 micromole/L; p= 0.003). Conclusion: This study shows that blood homocysteine level in recurrent pregnancy loss patients is significantly higher compared to normal fertile mothers. There is a strong association between hyperhomocysteinemia and RPL. J Enam Med Col 2021; 11(1): 10-17
... Spontaneous abortion cases in humans occur as a result of sophisticated interactions between a range of genetic factors and certain environmental conditions (Zetterberg, 2004 there is a relationship between (CT and TT) genotype MTHFR C677T and RPL (Shaima S. et al., 2018). ...
ABSTRACT: Abortion is the most common complication during pregnancy. The phenomenon
of thrombophilia is important in pregnant women and it has been associated with recurrent
pregnancy loss. Genotyping of single nucleotide polymorphisms (SNPs) of the genes involved in
thrombophilia may be useful.
There are many factors that affect abortion and recurrent miscarriage such as female
age and embryonic aneuploidy, antiphospholipid syndrome, parental structural
chromosomal abnormalities, uterine structural abnormalities, endocrine factors,
including thyroid function, polycystic ovary syndrome (PCOS) and prolactin,
immunological factors and progesterone supplementation, infection, lifestyle and
sperm DNA damage. One of the other factors that has been associated with recurrent
pregnancy loss (RPL) is inherited thrombophilia. The specific genotypes of several
SNPs have been associated with increased risk of recurrent miscarriage. In this project,
we aimed to evaluate the allelic frequencies of SNPs within seven genes that are
associated with thrombophilia in the Iraq-Erbil population. Thus, it was aimed to
determine the relationship between the genotypes of these SNPs and the number of
abortions, age and family history.
Blood samples were obtained from 50 women with recurrent miscarriages and 30
women who did not have any spontaneous abortions as control cases. Using PCRRFLP, SNPs within the Methylene Tetrahydrofolate Reductase (MTHFR) C677T and
A1298C, Plasminogen Activator Inhibitor-1 (PAI-1), Factor V Leiden, Prothrombin
G20210A, Factor XIII and Fibrinogen beta chain were genotyped.
The results of this study showed that there was no association between recurrent
miscarriage with age however the two genes MTHFR C677 and MTHFR A1298C were
related to family history. On the other hand, MTHFR C677T and PAI-1 (4G/5G) were
shown a significant association with recurrent pregnancy loss. More importantly, the
allelic frequencies in RPL and control cases showed statistically significant differences
for all the SNPs investigated. Thus, the results of this study may show the importance
of genetic testing in RPL patients. This study forms the basis of future studies and
further analyses including more number of patients will be designed.
Keywords: Recurrent miscarriage, MTHFR C677, MTHFR A1298C, PAI-1, gene
... Thus, the study of abortive material showed a significant increase in the risk of miscarriage (14 times) in the presence of the embryo alleles of the gene MTHFR 677T and / or 1298C in a homo-or heterozygous state. Given the important role of folic acid in the metabolism of nucleic acids, and hence in the processes of proliferation and differentiation, disruption of the folate cycle is extremely dangerous for rapidly dividing embryonic cells [13,14] Elevated homocysteine levels may be accompanied by the development of secondary autoimmune reactions and are currently considered as one of the possible causes of antiphospholipid syndrome. Thus, in a study by Brazilian scientists, in women with a history of miscarriage and the presence of antiphospholipid syndrome, the frequency of the 677T allele (40.3%) was significantly higher than in the control. ...
... This indicates the independent occurrence of C677T and A1298C polymorphisms. It is possible that the presence of two substitutions in the MTH-FR gene on one chromosome is lethal [14]. ...
The study of immunogenetic markers associated with the development of complications of pregnancy and perinatal pathology in newborns is of great practical importance for the development of preventive measures and maintaining the health of the baby in the future. Numerous studies in recent years have shown that the presence of genetic predisposition to certain diseases is associated with an increased risk of pregnancy complications (habitual miscarriage, placental insufficiency, late toxicosis), which leads to the implementation of perinatal pathology in later life.
... al., 2012]. MTHFR possibly plays a role in neural tube defects [Zetterberg, 2004]. Women with diabetes that have high hemoglobin A1C (HbA1C) levels in the first trimester are at risk of fetal loss and fetal malformation [Hanson, et. ...
This study was designed to find out gene polymorphisms associated with sporadic and recurrent early pregnancy loss in Russian women living in Central Russia. For the first time in Russia, our study has determined the genotype and allele frequencies for eight single nucleotide polymorphisms located in DNA methyltransferase genes (DNMT3B rs2424913, DNMT3B rs1569686, DNMT3A rs7590760, DNMT1 rs2228611, DNMT1 rs8101626, DNMT3L rs2276248, and DNMT3L rs2070565) and in SYCP3 gene (SYCP3 rs769825641) among women with early pregnancy loss. We have also assessed the following gene polymorphisms in genes of prothrombin (FII rs1799963), Factor V (FVL rs6025, Leiden), VEGFA (rs3025039, rs699947), MTHFR (rs1801133, rs1801131), MTR rs1805087, and MTRR rs1801394 previously reported underlying EM to elucidate their contribution to early miscarriage among our research participants. To determine the prevalence of all the studied gene polymorphisms in Russian women and make a comparison between the polymorphisms in DNMT1, DNMT3A, DNMT3B, DNMT3L, SYCP3 genes with the prevalence of gene polymorphisms, recommended previously as for genetic predictors recurrent early miscarriage.
MATERIALS AND METHODS OF THE RESEARCH: Characteristics of Study groups. This thesis is made of two types of studies, analytical case-control study in which the women with the idiopathic early miscarriage that occurred before 12th week of gestation, were compared with the healthy women that had normal pregnancies and didn’t have any previous history of adverse pregnancy outcome, and population study in which women without any previous history of normal pregnancy or early pregnancy loss were analyzed. 237 Russian women from Central Russia were enrolled in the study, out of them, 100 women experiencing idiopathic early miscarriage (EM) with an average age of 31.5±4.9 years, as a case group, 56 healthy women with an average age of 29.2±3.5 years, as a control group for the case-control study and 81 women with a mean age of 22.3±2.6 years, as a population group for the population study. On the basis of a number and successiveness of early miscarriage occurrence, the case group was classified into two groups: sporadic early miscarriage (SEM) consisted of 50 women, refers to the women that had non-repetitive random early miscarriage, the average age was 30.81±5.9 years, and recurrent early miscarriage (REM) consisted of 50 women, refers to the women that had recurrent consecutive early miscarriages of two or more, the average age was 31.1±5.5 years. The age both of the control and case groups were matched and no significant difference was noticed. The recurrent early miscarriage group was further subdivided into primary REM made of 21 women, refers to those who had never had any previous normal pregnancy before the initial onset of REM, and secondary REM made of 29 women, had had at least one normal pregnancy before the initial onset of REM. Genomic DNA extraction was carried out from the peripheral blood by the standard procedure with the use of a commercially available kit (Syntol, Russia). DNA genotyping. The studied gene polymorphisms, DNMT3B rs1569686, DNMT3B rs2424913, DNMT1 rs2228611, DNMT1 rs8101626, DNMT3A rs7590760, DNMT3L rs2070565, DNMT3L rs2276248 were genotyped by the method of Restriction Fragment Length Polymorphism-Polymerase Chain Reaction (RFLP-PCR). The amplified products were cleaved by using convenient restriction enzymes (SibEnzyme, Russia). SYCP3 rs769825641 polymorphism was genotyped by using Allele-specific PCR. The given fragments were separated and visualized by electrophoresis in 3.0 % agarose gel. The gene polymorphisms, MTHFR rs1801131, MTHFR rs1801133, MTRR rs1801394, MTR rs1805087, VEGFA rs699947, VEGFA rs3025039, FVL rs6025, FII rs1799963 were genotyped by using the Real time-PCR method with utilizing commercially available genotyping kits (Syntol, Russia).
CONCLUSION: The studies included in this thesis were designed to investigate the genotype and allele frequencies for some gene polymorphisms (DNMT3B rs2424913, DNMT3B rs1569686, DNMT3A rs7590760, DNMT1 rs2228611, DNMT1 rs8101626, DNMT3L rs2276248, DNMT3L rs2070565, SYCP3 rs769825641, FII rs1799963, FVL rs6025, MTHFR rs1801131, MTHFR rs1801133, MTRR rs1801394, MTR rs1805087, VEGFA rs699947, and VEGFA rs3025039) and detect the association between them and early pregnancy loss in Russian women. The results of the studies allow us to draw the following conclusions: 1. The minor allele T and the minor homozygous genotype TT for DNMT3B rs2424913 polymorphism are associated with the increased risk of early miscarriage. 2. The minor allele G and the minor homozygous genotype GG for DNMT1 rs2228611 polymorphism show a significant association with recurrent early miscarriage, whereas the homozygous genotype GG for DNMT1 rs8101626 is associated with both sporadic and recurrent early pregnancy loss. 3. The heterozygosity for VEGFA rs699947 polymorphism predisposes to recurrent early miscarriage. 4. The heterozygous genotype for SYCP3 rs769825641 polymorphism is significantly associated with sporadic early miscarriage. 5. No significant association was observed between DNMT3A rs7590760, DNMT3L rs2276248 polymorphisms, and early pregnancy loss. 6. The distribution of genotypes and alleles for DNMT3B rs2424913, DNMT1 rs2228611, DNMT1 rs8101626, and SYCP3 rs769825641 among Russian women is comparable with that for common polymorphisms associated with increased risk of pregnancy.
... The importance of supplementation before conception, in women who are still planning a pregnancy, with vitamin B12 and folate could perhaps reduce miscarriage incidence. 9 Alternative genes have also been correlated with pregnancy loss. Mutations of the SCO2 gene (cytochrome c oxidase (COX) assembly gene) located on chromosome 22, have been identified in the heterozygous state in aborted fetuses and are suggested to cause miscarriage. ...
... The balance between homocysteine and folate is an important factor in pregnancy. Homocysteine causes defects in both the neural tube and heart in embryos and increases the risk of growth abnormalities and retardation of somite development in mouse and rat embryos [29]. During pregnancy, homocysteine is a sulfur amino acid and a byproduct of the methionine bio-synthesis pathway [30]. ...
Numerous studies have examined the genetic association of vascular endothelial growth factor (VEGF) single nucleotide polymorphisms (SNPs) with recurrent pregnancy loss (RPL). However, of the four known SNPs in the 3′-untranslated region (3′-UTR) of VEGF, three SNPs—namely rs3025040 (1451C>T), rs10434 (1612G>A), and rs3025053 (1725G>A)—remain poorly characterized with regard to RPL. Herein, we evaluated the association between these three SNPs in the VEGF 3′-UTR and RPL susceptibility. We analyzed VEGF 3′-UTR gene variants in with and without RPL using TaqMan allelic discrimination. There were significant differences in the genotype frequencies of 1612G>A (GA: adjusted odds ratio (AOR), 0.652; 95% confidence interval (CI), 0.447–0.951; p = 0.026) and 1725G>A (GA: AOR, 0.503; 95% CI, 0.229–0.848; p = 0.010) in RPL patients vs. controls. Our results indicate that the 1612G>A and 1725G>A polymorphisms in the 3′-UTR of VEGF are associated with RPL susceptibility in Korean women. These data suggest that VEGF 3′-UTR polymorphisms may be utilized as biomarkers for the detection of RPL risk and prevention.
... Homocysteine induces embryonic defects in both the neural tube and the heart. It also increases the risk of growth retardation and somite development abnormalities in mouse and rat embryos [33]. Homocysteine may be involved in the pathogenesis of idiopathic RIF [34]. ...
Purpose
Vitamin B12 (cobalamin, Cbl) plays a role in the recycling of folate, which is important in pregnancy. Transcobalamin II (TCN2) and transcobalamin receptor (TCblR) proteins are involved in the cellular uptake of Cbl. TCN2 binds Cbl in the plasma, and TCblR binds TCN2-Cbl at the cell surface. Therefore, we investigated the potential association between polymorphisms in Cbl transport proteins, TCN2 and TCblR, and recurrent implantation failure (RIF) susceptibility.
Methods
The genotypes of TCN2 67A>G, TCN2 776C>G, and TCblR 1104C>T were determined for RIF patients and healthy controls using a polymerase chain reaction restriction fragment length polymorphism assay. Additionally, statistical analysis was performed to compare the genotype frequencies between RIF patients and controls.
Results
The TCN2 67 polymorphism AG type was associated with RIF risk. Some allele combinations that contained the TCN2 67 polymorphism G allele were associated with increased RIF risk, whereas other allele combinations that contained the TCblR 1104 polymorphism T alleles were associated with decreased RIF risk. In genotype combination analysis, two combinations containing the TCN2 67 polymorphism AG type were associated with RIF risk.
Conclusion
Our study showed that the polymorphisms of TCN2 and TCblR are associated with RIF and are potential genetic predisposing factors for RIF among Korean women. Additionally, our findings support a potential role for TCN2 and TCblR in RIF among Korean women. However, further studies are required to investigate the role of the polymorphisms in those proteins and RIF because the roles of the TCN2 and TCblR polymorphisms in RIF are not clear.
... Inherited thrombophilia is well known cause of spontaneous pregnancy loss [11,12] , Folate is important for normal RNA and DNA synthesis and it is required for homocysteine metabolism. It is also important for normal fetal growth and development, in certain situations like pregnancy folate requirements are increased [13] homocysteine level in the body is affected mainly by folate and vitamin B12 intake in diet, and polymorphism in genes which encode enzymes or transport proteins involved in the folate-and vitamin B12-dependent homocysteine metabolism [14,15] . Decreased folate intake will affect homocysteine metabolism and will lead to an increase in homocysteine level in circulation [16] . ...
Background: missed abortion is a common problem, thrombophilia is a common cause of missed abortion either recurrent or not Aim of the work: to correlate presence of MTHFR gene mutation in patients with missed abortion Patients and methods: the study included 200 patients divided into 2 groups; study group included 100 patients with history of missed abortion, and control group included 100 case with no history of missed abortion. Results: of 200 patients only 44 was having MTHFR gene mutation, 34 of them was present in case group while 10 only in control group. Conclusions: MTHFR gene mutation is acommon cause of missed abortion either recurrent or not
... On the other hand, some meta-analyses have shown that Asian women carriers of the MTHFR 677T allele have a higher risk of recurrent pregnancy loss, but such association was not observed in Caucasian women or mixed subgroups although the number of studies included was low (Wu et al., 2012;Cao et al., 2013). However, few studies on the link between MTHFR polymorphisms and non-recurrent pregnancy loss have been conducted, and generally no association has been found (Zetterberg, 2004). Most of such studies have examined the effect on late pregnancy loss (after week 19), which could have a different etiology from that of early loss. ...
... The frequency of SA (6.9%) was similar to that reported in other prospective studies conducted in Mexico (Rodríguez-Guillén et al., 2009;Borja-Aburto et al., 1999). Our results are consistent with those of meta-analysis that found no association between homozygosity for the MTHFR C > T mutation and non-recurrent pregnancy loss (Rey et al., 2003;Zetterberg, 2004). However, they are not consistent with the findings of the prospective study by Rodríguez-Guillén et al. (2009), who found an increased risk of SA in Mexican women with the 677TT genotype compared with those with the 677CC/CT genotype (OR = 5.0, 95% CI: 1.2, 20.9). ...
MTHFR is a key enzyme in folate metabolism. Some genetic polymorphisms code for a less efficient enzyme, increasing serum concentrations of homocysteine. This has been associated with inadequate feto-maternal circulation and increased risk of spontaneous abortion. Paroxonase 1 (PON1) is a multifunctional enzyme that can detoxify homocysteine through its homocysteine thiolactonase activity. We evaluate the association between MTHFR 677 C>T polymorphisms and non-recurrent spontaneous abortion and its interaction with PON1 polymorphisms involved in homocysteine metabolism in women living in floricultural areas in Mexico. Sociodemographic, reproductive history, folic acid consumption during pregnancy and environmental exposure data of 264 women who had been pregnant sometime during the 10 years prior to study enrolment were collected. MTHFR 677 C>T, PON1 192Q>R and PON1 55L>M genotypes were determined by PCR amplification. Information on pregnancy outcome and maternal genotypes was obtained for 484 pregnancies: 34 non-recurrent spontaneous abortions (gestational age < 20 weeks) and 450 controls. GEE models were used to evaluate the association between MTHFR polymorphism and non-recurrent spontaneous abortion, and its interaction with PON1 polymorphisms. After adjusting for potential confounders, no significant association was found between the MTHFR 677 C>T maternal polymorphism and non-recurrent spontaneous abortion (OR CT vs CC= 0.39, 95% CI: 0.14-1.05; OR TT vs CC = 0.63, 95% CI: 1.22–1.80). No interactions with PON1 192Q>R or PON1 55L>M polymorphisms were identified (p for interaction = 0.88 and 0.41, respectively). PON1 55L>M maternal polymorphism was associated with higher risk of spontaneous abortion (OR LM/MM vs LL = 4.14, 95% CI: 1.49–11.54). Our results do not demonstrate an interaction between the MTHFR 677 C>T and PON1 192Q>R or PON1 55L>M maternal polymorphisms neither an independent association of MTHFR 677 C>T polymorphism with non-recurrent spontaneous abortion, whereas PON1 55LM/MM maternal genotype increase the odds of this event.
