Methylenetetrahydrofolate reductase and transcobalamin genetic polymorphisms in human spontaneous abortion: biological and clinical implications

Abstract

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. There are several genetic polymorphisms that are associated with defects in folate- and vitamin B12-dependent homocysteine metabolism. The methylenetetrahydrofolate reductase (MTHFR) 677C>T and 1298A>C polymorphisms cause elevated homocysteine concentration and are associated with an increased risk of NTD. Additionally, low concentration of vitamin B12 (cobalamin) or transcobalamin that delivers vitamin B12 to the cells of the body leads to hyperhomocysteinemia and is associated with NTD. This effect involves the transcobalamin (TC) 776C>G polymorphism. Importantly, the biochemical consequences of these polymorphisms can be modified by folate and vitamin B12 supplementation. In this review, I focus on recent studies on the role of hyperhomocysteinemia-associated polymorphisms in the pathogenesis of human spontaneous abortion and discuss the possibility that periconceptional supplementation with folate and vitamin B12 might lower the incidence of miscarriage in women planning a pregnancy.

Folate pathway and nonsyndromic cleft lip and palate

“…Perturbation of gene expression with the creation of a new DNA binding site could result in an increase in homocysteine levels leading to hyperhomocysteinemia. Hyperhomocysteinemia has been implicated as a risk factor for other congenital anomalies such as NTDs, heart defects, and neurocristopathies (Brauer and Tierney, 2004; Rosenquist et al, 1996; Selhub, 2008; Zetterberg, 2004). Hyperhomocysteinemia could either directly or indirectly disrupt a multitude of cellular processes important to lip and palate development including cellular proliferation, apoptosis, migration and DNA synthesis (Brauer and Tierney, 2004; Knott et al, 2003; Zetterberg, 2004).…”

“…Hyperhomocysteinemia has been implicated as a risk factor for other congenital anomalies such as NTDs, heart defects, and neurocristopathies (Brauer and Tierney, 2004; Rosenquist et al, 1996; Selhub, 2008; Zetterberg, 2004). Hyperhomocysteinemia could either directly or indirectly disrupt a multitude of cellular processes important to lip and palate development including cellular proliferation, apoptosis, migration and DNA synthesis (Brauer and Tierney, 2004; Knott et al, 2003; Zetterberg, 2004). Indeed, in a handful of studies, high plasma homocysteine levels have been observed in mothers after the birth of an infant with a clefting abnormality (Knott et al, 2003; Rubini et al, 2005b; Verkleij-Hagoort et al, 2007; Wong et al, 1999).…”

Genetic and Epigenetic Contributions to Human Nutrition and Health: Managing Genome–Diet Interactions

“…Humans exhibit high rates of fetal loss (43), with approximately 75% of human conceptions lost spontaneously before term, half of which occur before the first 3 weeks of gestation and generally are unnoticed because many embryos fail to implant (40–42,44). Maternal folate status, impaired folate metabolism as evidenced by elevated plasma homocysteine, and SNPs in folate-related genes that are associated with risk for birth defects have also been associated with risk for miscarriage (45–51). In a recent study, increased maternal folate status also increased the likelihood of twin births after in vitro fertilization (52).…”

The impact of low molecular weight heparin on obstetric outcomes among unexplained recurrent miscarriages complicated with methylenetetrahydrofolate reductase gene polymorphism

“…Patients homozygous for MTHFR C677T showed about 30% of normal enzyme activity while heterozygosity demonstrates 65% of normal enzyme activity. In contrast, such reduction in enzyme activity in women with MTHFR A1298C polymorphism was not demonstrated [9,10]. It would be reasonable then to assume that the A1298C type of polymorphism does not influence the homocysteine levels, hence it should not be linked to unexplained RM.…”