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. Current work includes examining the role of another folate pathway gene, dihydrofolate reductase. The enzyme produced by this gene is critical in the conversion of folic acid, a synthetic form of folate, into the active form, tetrahydrofolate. It is also important in converting dihydrofolate to tetrahydrofolate in the normal folate pathway. Our investigation, recently published, revealed mixed results. We observed an association with NTDs signal in an Irish cohort but failed to replicate this in a separate, smaller UK cohort. We also assessed DHFR2 as a potential QTL for biomarkers of folate one carbon metabolism and as a eQTL. Upon correction for multiple tests, these analyses did not show any significant correlations with serum folate, red cell folate, plasma total homocysteine, plasma formate, or tissue mRNA expression levels. Thus, the role of DHFR2 remains to be determined. 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. We also collaborated in an investigation of folic acid labeling, suggesting ways to make it clearer and more consistent with RDA data. We anticipate continuing to explore genomic associations with NTDs and biochemical pathways in the future.