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DNA合成中嘌呤和嘧啶生产的重要基因，是NTDs的危险因素。我们现在在两项研究中表明，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. We have now shown in two studies that mothers who have the R653Q variant of this gene are at increased risk of having a child with an NTD. We have examined the relationship between variants in the tumor protein p53 (TP53) gene and NTDs because TP53 is important in implantation and normal neural tube development in animals. In the process, we also created a high resolution linkage disequilibrium map of the TP53 genomic region using 21 markers found in our Irish population. Alleles of three non-coding regions were associated with NTD risk, one in cases and two in mothers. Because multiple comparisons were made, additional investigation is required. In the process of identifying the risk genes reported above, we have also shown that numerous folate and vitamin B12 related genes do not appear to be risk factors for NTDs in the Irish population. Because we have a large, genetically homogeneous population,our work has clarified the importance of genes for which there was weak or conflicting evidence for a role in NTDs. We have expanded our genetic investigation greatly by using Illumina technology to examine 1536 single nucleotide polymorphisms (SNPs) from candidate genes to identify other genes associated with NTDs. Cases, their mothers, their fathers (triads), and unaffected controls have been genotyped. The Illumina run has been completed and the SNPs that showed the strongest association with NTDs have been identified. A second, confirmatory group of triads and unaffected controls has been genotyped for these and related SNPs. The data are currently being edited and will be analyzed. Cleft lip with or without cleft palate (CLP)and cleft palate only (CPO) have an inherited component and, many studies suggest, a relationship with folate. We gathered 536 CLP triads and 426 CPO triads with unaffected control subjects to determine whether folate, or folate related genes, were risk factors for clefts. We studied the following well known single nucleotide polymorphisms (SNPs): methylenetetrahydrofolate reductase (MTHFR) 677 C->T and 1298 A->C, methylenetetrahydrofolate dehydrogenase I (MTHFD) 1958 G->A, and transcobalamin II (TCII) 776 C->G. We found that CPO mothers were more likely to have the MTHFR TT variant of 677 C->T and the MTHFD AA variant of 1958 G->A. The MTHFD AA variant was also significantly more common in both cases with CLP and their mothers. These findings should be explored in more detail because multiple comparisons were performed. Additional candidate genes will be tested for associations with clefts in the future.