NICHD Health Research Board Of Ireland Neural Tube Defects Study

流行病学处正在与卫生研究委员会和爱尔兰都柏林三一学院合作开展一些出生缺陷研究。这些研究的主要目的是确定叶酸和出生缺陷之间的关系。迄今为止研究的出生缺陷包括神经管缺陷（NTDs）、唇裂、先天性心脏缺陷、唐氏综合症和脐膨出。这些研究主要集中在叶酸代谢领域的生化因素，以及与出生缺陷相关的叶酸相关基因的基因突变。最近的工作已经扩展到包括与出生缺陷有关的生化途径。

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. Other ongoing work explores the relevance of variants in genes that affect vitamin B12, another important vitamin related to NTDs because of its role in methylation. 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. We anticipate continuing to explore genomic associations with NTDs and biochemical pathways in the future.