This link between folate and choline metabolism selleck catalog makes PEMT an interesting candidate gene, and interactions between PEMT SNPs have been reported to be asso ciated with NTDs. In a case control study, single SNP effects were not observed, although some compound genotypes for PEMT rs7946 and PEMT rs897453 were associated with decreased NTD risk. The latter vari ant was not directly tested in the current study, and no association for PEMT rs7946 was observed in this Irish sample. However, one related SNP pair and two other SNPs in PEMT falling in the same haplotype block showed NTD associ ation in the current study, sug gesting a role for this gene in NTD risk. Unlike the other three SNPs that exhibited case effects, the least related SNP in this block was positive for maternal effects by three tests of association.

This intronic SNP is in strong r2 LD with 6 other Inhibitors,Modulators,Libraries intronic SNPs, making it difficult to speculate about its function. It is also difficult to discern whether the associated SNPs in this block represent independent signals for case risk and for maternal risk, or whether a single signal for a case effect is being detected. There fore, further studies on the variation of this gene and NTDs are Inhibitors,Modulators,Libraries warranted. MFTC transports folate from the cytoplasm into the mitochondria. Some folate metabolic reactions occur in both the cytoplasm and in mitochondria via compartment specific enzymes. The mitochondrion pro duces the majority of the one carbon units Inhibitors,Modulators,Libraries used by the cell. As the genes coding for these mitochondrial enzymes have been identified, they have been shown to be intriguing and relevant candidates for NTD studies.

For example, we previously reported that the gene encoding 5, 10 methylene tetrahydrofolate de hydrogenase 1 like contains a polymorph ism associated with NTDs. Genetic variation affecting mitochondrial folate transport may also con tribute to NTDs, as seen by our finding that 5 of 11 tested MFTC SNPs showed association with NTD risk in cases. This Inhibitors,Modulators,Libraries gene falls in a region of very high D LD. the haplotype block containing these five SNPs extends 92 kb and contains two other genes DCAF13 and CTHRC1. Any SNP in this large haplotype block could be the causative variant driving the observed associations. As the only coding SNP in MFTC, the best candidate is rs17803441. However, as arginine and histidine are both polar, basic amino acids, this is a fairly conservative change.

We observed a minor allele frequency of 0. 07 in this study. Conservation of the more common arginine residue is observed in chimp, wolf, cow, mouse, rat and zebrafish, but not in chicken or invertebrates. All of the SNPs in high LD with MFTC rs17803441 in this block Inhibitors,Modulators,Libraries are intronic or intergenic. This SNP also had the lowest p value for any test of associ ation of all SNPs tested in this study. It would be of great interest to determine in neverless an independent population whether it contributes to NTD risk.