522. THE ASSOCIATION OF FOLATE PATHWAY ENZYME POLYMORPHISMS AND PREGNANCY OUTCOME

Abstract

The folate, vitamin B12 and vitamin B6 (one-carbon) metabolic pathway is essential for the synthesis of precursors used in DNA synthesis, repair, and methylation. We hypothesise that single nucleotide polymorphisms in genes encoding enzymes in this pathway can disrupt these processes leading to adverse pregnancy outcomes. We investigated associations of six candidate polymorphisms in five genes related to one-carbon metabolism with risk for adverse pregnancy outcome in 586 nulliparous Caucasian couples with normal fertility. Chi-square analysis was used to compare genotype frequencies with pregnancy outcomes. Pregnancies were classified as healthy (n=261), preeclampsia (PE, n=38), gestational hypertension (GHT, n=32), small-for-gestational-age (SGA, n=60) and PE+SGA (n=22). Associations between maternal, paternal and neonatal genotypes with customised birthweight centiles and placental weight were determined using ANOVA with SIDAK post-hoc analyses. The maternal MTR 2756 G allele was associated with decreased placental weight (–87g, P=0.040). Both paternal and neonatal MTR 2756 G alleles were associated with lower birthweight (–12%, P=0.028 and –10%, P=0.039) while the latter was also associated with PE+SGA (P <0.000). Neonatal MTRR GG genotype was associated with GHT and PE with SGA (P=0.033, P=0.011). Neonatal MTHFD1 GG genotype was twice as frequent in PE and GHT (P=0.037; P=0.019) while neonatal TCN2 GG genotype doubled in SGA (P=0.042) compared with healthy pregnancies. Our findings indicate that genetic variation in multiple one-carbon metabolism genes may influence risk of adverse pregnancy outcome. MTR with cofactor vitamin-B12, catalyses the methylation of homocysteine to methionine. Formation of methionine through this pathway is important for synthesis of phospholipids, proteins, myelin, DNA, RNA and S-adenosyl methionine. TCN2 encodes the vitamin-B12 transport protein and MTHFD1 catalyses the conversion of one-carbon derivatives of tetrahydrofolate, which are substrates for methionine, thymine and purine synthesis and are important for healthy placental and fetal development. Larger studies are needed to further examine gene/gene and gene/diet interactions in this pathway.