The genetics of folate and vitamin B12 metabolism relate

分子发病机制的研究重点是定义基因的变化，这些变化是遗传对常见疾病（如癌症和出生缺陷）的易感性的基础。叶酸代谢的改变与肿瘤形成和出生缺陷有关。叶酸基因也参与DNA的甲基化和适当的大脑功能。.我们正在寻找与叶酸、蛋氨酸和同型半胱氨酸代谢相关的基因的遗传变异。患有癌症或脊柱裂（神经管缺陷的一种形式）的个体将接受这些变异的测试。在患病个体中发现的频率较高的变异将有助于我们识别与风险相关的基因。在过去，我们已经测试了超过15个基因的变异，这些变异可能会干扰叶酸代谢，因此与神经管缺陷儿童的风险增加有关。我们发现，这些基因之一TC 2的变异似乎会影响怀孕期间血液中维生素B12的水平。这一发现可能与出生缺陷有关，也可能有助于解释为什么一些老年人会因维生素B12缺乏而贫血和出现神经系统症状。我们还发现，携带第二个基因MTHFD 1特定变体的母亲，生育神经管缺陷儿童的风险增加50%。这种以前未描述的变异可能导致高达25%的神经管缺陷。大约五分之一的人携带这些风险因素之一。我们最近确定这种特殊的变异也是胎盘脱垂的一个危险因素，胎盘脱垂是流产和妊娠中期流产的常见原因。我们已经在实验室中重新创建了这些基因，目前正在使用一个实验系统来确定这些变体如何改变这些蛋白质的功能。 去年完成的实验表明，不同形式的TC 2以不同的亲和力结合维生素B12。这些数据可以解释我们和其他人在血浆维生素B12水平上观察到的差异。我们已经扩大了这些研究，包括负责将维生素B12转运到细胞中的分子。我们有初步的数据表明，这种转运蛋白的变异与NTD患儿的风险有关。我们目前正在进行实验，旨在确定该基因中的许多变体中的哪一个实际上导致了风险增加。 在过去的一年里，我们开始研究叶酸，维生素B12和DNA甲基化之间的关系。人们对DNA甲基化的个体间变异知之甚少。我们开发了一种检测方法，可以通过DNA测序来测量甲基化的程度。我们目前正在评估这项技术。如果成功的话，这种方法将使我们能够以高分辨率绘制基因组中的甲基化位点。 对叶酸/维生素B12代谢途径中基因功能的详细了解将增加我们对神经管缺陷的理解，并可能有助于指导营养补充领域的公共卫生政策。

Research in the Molecular Pathogenesis is focused on defining changes in the genes that underlie inherited susceptibilities to common diseases such as cancer and birth defects. Changes in folate metabolism are correlated tumor formation and birth defects. Folate genes are also involved in the methylation of DNA and proper brain function. . We are searching for genetic variants in genes related to folate, methionine and homocysteine metabolism. Individuals affected with cancer or Spina Bifida (one form of neural tube defects) will be tested for these variants. Variants found at higher frequency in individuals with disease will help us identify genes associated with risk. In the past we have tested more than 15 genes for variants that might perturb folate metabolism and therefore be associated with an increase risk of having a child with an neural tube defect. We found that variants in one of these genes, TC2, appear to affect the levels of vitamin B12 in the blood during pregnancy. This finding may be related to birth defects and also may help to explain why some elderly individuals become anemic and suffer neurological symptoms from vitamin B12 deficiency. We also found that mothers carrying a specific variant in a second gene, MTHFD1, have a 50% increased risk bearing a child with a neural tube defect. This previously un-described variant may be responsible for up to 25% of all neural tube defects. Approximately one in five individuals in the population carry one of these risk factors. We recently determined that this particular variant was also an risk factor for placental abruption a common cause of miscarriage and for misscarriages that occur in the second trimester. We have re-created these genes in the laboratory and are currently using an experimental system to determine exactly how these variants alter the function of these proteins. Experiments completed in the last year have revealed that the different forms of TC2 bind vitamin B12 with different affinities. These data may explain the differences that we and others observe in plasma levels of vitamin B12. We have expanded these studies to include the molecule responsible for transporting vitamin B12 into the cell. We have preliminary data that suggests that variants in this transporter are associated with a risk of having a child with an NTD. We are currently carrying out experiment aimed determining which of the many variants in this gene is actually causing the increased risk. In the past year we began to investigate the relationship between folate, vitamin B12 and DNA methylation. Little is known about inter-individual variation in DNA methylation. We developed an assay that allows us to measure the extent of methylation by carrying out DNA sequencing. We are currently evaluating this technique. If sucessful, this method will allow us to map methylation sites in the genome at high resolution. A detailed knowledge of the function of the the genes in the folate/vitamin B12 metabolic pathways will add to our understanding of neural tube defects and potentially help guide public health policy in the area of nutritional supplementation.