In our study, an increased risk of NTD was observed for 1958G>A of MTHFD1 (AA vs. GG: OR=2.63, 95% CI=2.61-5.70; AA vs. GG+GA: OR=2.10, 95% CI=1.07-4.14; A vs. G: OR=1.62, 95% CI=1.11-2.36).
Gene variants in the folate metabolic pathway (e.g., MTHFR rs1801133 (677 C > T) and MTHFD1rs2236225 (rs2236225" genes_norm="1788;4522">R653Q)) have been found to increase NTD risk.
We conclude that genetic variation in the MTHFD1 gene is associated with an increase in the genetically determined risk that a woman will bear a child with NTD and that the gene may be associated with decreased embryo survival.
We have established that the MTHFD1 1958G>A polymorphism has a significant role in influencing a mother's risk of having an NTD-affected pregnancy in the Irish population.
In summary, our results indicate that heterozygosity and homozygosity for the MTHFD1 1958G > A polymorphism are genetic determinants of NTD risk in the cases examined.
Our research provides the first evidence supporting a paternal, rather than a maternal, transmission bias of MTHFD1G1958A variant for NTD susceptibility in the offspring.
For MTHFD1rs2236225 polymorphism, mothers having GA genotype and A allele exhibited an increased risk of NTDs in the offspring (OR = 2.600, 95%CI: 1.227-5.529; OR = 1.847, 95%CI: 1.047-3.259).
For rs2236225 within MTHFD1, children with allele A or genotype AA had a high NTDs risk (OR=1.500, 95%CI=1.061~2.120; OR=2.862, 95%CI=1.022~8.015, respectively).
Having previously identified a polymorphism within the cytoplasmic folate enzyme, MTHFD1, as a maternal risk factor for NTDs, we considered the more recently identified mitochondrial paralogue, MTHFD1L, as a candidate gene for NTD association.
We conclude that genetic variation in the MTHFD1 gene is associated with an increase in the genetically determined risk that a woman will bear a child with NTD and that the gene may be associated with decreased embryo survival.
We have established that the MTHFD1 1958G>A polymorphism has a significant role in influencing a mother's risk of having an NTD-affected pregnancy in the Irish population.
In summary, our results indicate that heterozygosity and homozygosity for the MTHFD1 1958G > A polymorphism are genetic determinants of NTD risk in the cases examined.