NICHD Health Research Board Of Ireland Neural Tube Defects Study

Eunice Kennedy Shriver National Institute Of Child Health & Human Development

Investigators

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Abstract

The Epidemiology Branch is conducting a number of birth defect studies in collaboration with the Health Research Board and Trinity College, Dublin, Ireland. The main objective of these studies is to determine the relationship between folate and birth defects. The birth defects studied to date are neural tube defects (NTDs), oral clefts, congenital heart defects, Down syndrome and omphalocele. These studies focus on biochemical factors in the area of folate metabolism, and on genetic mutations in folate related genes associated with birth defects. Recent work has expanded to include the biochemical pathways related to birth defects. Neural tube defects (NTDs) are common birth defects (1 in 1000 pregnancies in the US and Europe) that have complex origins, including environmental and genetic factors. A low level of maternal folate is one well-established risk factor, with maternal periconceptional folic acid supplementation reducing the occurrence of NTD pregnancies by 50-70%. The role of folic acid is very well established in preventing NTDs. It is also known that genetic factors are important based on family studies. To date only a few genetic variants have been shown to be important. This research has been hindered by the lack of data on how genetic variants affect folate status in the population. We conducted both candidate gene analyses and genome wide association studies in 2232 young subjects from a genetically Irish background. We measured serum folate, red cell folate and total plasma homocysteine. Our genome wide association data have been used in numerous collaborations. Most recently they were part of a mega-analysis led by the International League Against Epilepsy Consortium on Complex Epilepsies. Altered vitamin B6 metabolism due to pathogenic variants in the gene PNPO causes early onset epileptic encephalopathy, which can be treated with high doses of vitamin B6. We recently reported that single nucleotide polymorphisms (SNPs) that influence PNPO expression in the brain are associated with genetic generalized epilepsy (GGE). However, it is not known whether any of these GGE-associated SNPs influence vitamin B6 metabolite levels. We found that 84 GGE-associated SNPs influence expression levels of PNPO in the brain as well as in blood. However, these SNPs were not associated with vitamin B6 metabolism in plasma. Our work on folate has expanded into areas beyond biochemistry and genetics. We recently collaborated on a commentary discussing the possible role of unmetabolized folic acid in allergic conditions. Reviewing the evidence, we concluded that the data fail a critical test for causality. The mix of positive and negative studies fails the consistency test. The findings are not specific to any outcome, although this is not critical. The findings, far from being strong, include beneficial as well as harmful effects of prenatal FA exposure. In summary, allergic disease in infancy comprises a heterogeneous group of skin and airway conditions that range from uncomfortable and distressing both for the children and their parents to life-threatening anaphylaxis. FA exposure in pregnancy is not an important factor contributing to the reported increase in allergies. We also wrote a recent editorial analyzing the data suggesting an association between maternal folic acid intake and offspring autism spectrum disorder (ASD). Many studies have explored the influence of maternal folic acid (FA) intake on the risk of ASD in their offspring. There are 2 reasons to think that folate could be important in preventing ASD. First, maternal FA supplementation in the periconceptional period protects against the occurrence of neural tube defects, which are also neurodevelopmental disorders. Second, 1-carbon units derived from folate pathways are the main source of methyl groups for essential DNA and histone methylation reactions. Inadequate availability of such methyl groups could potentially affect gene expression, as suggested in studies exploring folate-related risk factors for ASD. In fact, most reports find that FA protects against ASD. We concluded that normal doses of FA have been shown to have a beneficial effect on development. A biological mechanism for an adverse effect has not been persuasively demonstrated, but the effect of UMFA inside the cell is largely unknown. Overall, the 2 studies on UMFA to date are contradictory, which speaks against a serious harmful effect, but the studies have serious limitations. Future investigations should focus on women exposed to high doses of FA during pregnancy and on the basic science of UMFA at the cellular level. We anticipate continuing to explore genomic associations with NTDs and biochemical pathways in the future.