Pregnancy loss and polymorphisms in folic acid genes

Folates are essential vitamins required for DNA synthesis and cell division to support the development of the placenta and the fetus. Indeed, folate metabolism is the “core” part of one-carbon metabolism, a set of interconnected pathways that supply methyl groups for the synthesis of nucleic acids, amino acids, and S-adenosylmethionine (SAM), the main intracellular methylating agent. DNA methylation reactions are essential for mammalian development, playing a pivotal role in cell differentiation, maintenance of the cellular identity during mitosis, and parent-of-origin imprinting. Common polymorphisms of genes involved in folate metabolism can lead to impairments in DNA synthesis or methylation, thereby affecting cell growth and differentiation, and have been often investigated as potential risk factors for pregnancy loss. Among them, the MTHFR 677C>T polymorphism has been extensively investigated, and recent meta-analyses support a potential role as a maternal risk factor for recurrent pregnancy loss (RPL), particularly in Asians and developing countries. For all the other investigated polymorphisms in folate-related genes, including MTHFR 1298A>C, MTR 2756A>G, MTRR 66A>G, RFC1-43T>C, RFC1 80A>G, RFC1 696C>T, TCN2 67A>G, TCN2 776C>G, MTHFD1 1958G>A, and CBS 844ins68, data are still controversial, likely due to the scarce number of available case-control studies. In addition, several investigators suggest that haplotypes or combined genotypes of genes required for folate metabolism could account for RPL, but additional studies are required to clarify this issue.