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。在过去的一年里，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TC2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。对这两个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 year 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 cuase of miscarriage. 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. A detailed knowledge of the function of these two genes will add to our understanding of neural tube defects and potentially help guide public health policy in the area of nutritional supplementation.