NICHD Health Research Board Of Ireland Neural Tube Defects Study

流行病学分支正在与健康研究委员会和爱尔兰都柏林的Trinity学院合作进行一些出生缺陷研究。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有神经管缺陷、口裂、先天性心脏缺陷、唐氏综合征和脐膨出。这些研究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，我们已经表明，高同型半胱氨酸是NTDs的危险因素，亚甲基四氢叶酸还原酶（MTHFR）基因677 C->T突变是NTDs的危险因素，小剂量的叶酸（100-200微克）可以提高红细胞叶酸水平，可以预防五分之一到几乎一半的NTDs。我们已经表明，亚甲基四氢叶酸还原酶（MTHFD），一个重要的基因在生产嘌呤和嘧啶的DNA合成，是一个危险因素NTDs。 我们现在已经在两项研究中表明，携带该基因R653 Q变体的母亲生育NTD儿童的风险增加。 我们已经研究了肿瘤蛋白p53（TP 53）基因和NTDs的变异之间的关系，因为TP 53在动物的植入和正常神经管发育中很重要。在这个过程中，我们还创建了一个高分辨率的连锁不平衡图谱的TP 53基因组区域使用21个标记在我们的爱尔兰人口。 三个非编码区的等位基因与NTD风险相关，一个在病例中，两个在母亲中。 由于进行了多重比较，因此需要进行额外的调查。 在识别上述风险基因的过程中，我们还发现许多叶酸和维生素B12相关基因似乎不是爱尔兰人群NTD的风险因素。 因为我们有一个大的，遗传同质的人口，我们的工作已经澄清了基因的重要性，有弱或相互矛盾的证据在NTD的作用。 我们已经扩大了我们的遗传学研究，通过使用Illumina技术来检查候选基因中的1536个单核苷酸多态性（SNP），以确定与NTD相关的其他基因。对病例、其母亲、父亲（黑社会）和未受影响的对照组进行基因分型。Illumina运行已经完成，并且已经鉴定了显示与NTD最强关联的SNP。 第二组，三联体和未受影响的对照组的确证性已被基因分型为这些和相关的SNP。 目前正在编辑数据，并将进行分析。 唇裂伴或不伴腭裂（CLP）和单纯腭裂（CPO）有遗传成分，许多研究表明，与叶酸有关。 我们收集了536个CLP三联体和426个CPO三联体与未受影响的对照受试者，以确定叶酸或叶酸相关基因是否是裂缝的危险因素。 我们研究了以下已知的单核苷酸多态性（SNP）：亚甲基四氢叶酸还原酶（MTHFR）677 C->T和1298 A->C，亚甲基四氢叶酸脱氢酶I（MTHFD）1958 G->A和转钴胺素II（TCII）776 C->G。 我们发现，CPO母亲更可能有MTHFR TT变异677 C->T和MTHFD AA变异1958 G->A。 MTHFD AA变体在CLP患者及其母亲中也明显更常见。 由于进行了多重比较，因此应更详细地探讨这些结果。 未来将测试其他候选基因与裂缝的关联。

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.