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。在过去，我们已经证明高同型半胱氨酸是NTDs的一个危险因素，亚甲基四氢叶酸还原酶（MTHFR）基因677C->T的突变是NTDs的一个危险因素，并且小剂量的叶酸（100-200微克）可以将红细胞叶酸提高到可以预防五分之一到几乎一半的NTDs的水平。我们已经证明亚甲基四氢叶酸还原酶（MTHFD）是ntd的危险因素，它是DNA合成中嘌呤和嘧啶的重要基因。携带该基因R653Q变体的母亲生下的孩子患NTD的风险更高。

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. In the past we have shown that elevated homocysteine is a risk factor for NTDs, that a mutation in the methylenetetrahydrofolate reductase (MTHFR) gene 677C->T is a risk factor for NTDs, and that a small dose of folic acid (100-200 micrograms) can raise red cell folate to levels that can prevent a fifth to almost a half of NTDs. We have shown that methylenetetrahydrofolate reductase (MTHFD), an important gene in the production of purine and pyrimidine for DNA synthesis is a risk factor for NTDs. Mothers who have the R653Q variant of this gene are at increased risk of having a child with an NTD. We have expanded our work on MTHFD, confirming in a second population that the MTHFD R653Q variant is a maternal risk factor for NTDs. We have examined other polymorphisms and variants related to folate metabolism as potential NTD risks. The reduced folate carrier is essential for transfer of folate into cells. A variant of the enzyme gene, H27R, has been reported to be a risk factor for NTDs, but this is uncertain. We stuied this variant in a large Irish population and showed that it was unrelated to NTDs in cases, their mothers and their fathers. Both the MTHFR C677T and A1298C variants have been reported to reduce the risk for some cancers. The biochemical effect of the MTHFR C677T variant is clear--it reduces folate stores; however, the biochemical effect of the MTHFR A1298C variant is unclear, perhaps because it is in linkage dysequilibrium with the MTFHR 677C wild type SNP. We were able to measure the effect of MTHFR A1298C independently of the MTHFR 677 effect, showing the the A1298C variant produces increased cellular (red cell) folate levels. This is a rare example of SNPs on the same exon producing opposite effects and it suggests that MTHFR 1298C influences cancer risk by a different mechanism than MTHFR 677T. We continue to investigate the role of other genes as NTD risk factors. We recently explored the role of another critical folate enzyme gene, dihydrofolate reductase as a risk factor for NTDs. Previous work did not show a protective effect of a 19bp intron deletion in mothers of NTD cases. Our study demonstrated that in the Irish population either one or two copies of the allele was significantly protective (p=.01) in mothers. There was a small increase in expression, a 1.5 fold increase in mRNA, as well. The difference did not reach statistical significance. Thus, the presence of the 19bp intron deletion may be protective against NTDs when present in mothers.