The contribution folate and vitamin B12 genes to disease.

叶酸和维生素 B12 基因对疾病的贡献。

• 批准号: 7734875
• 负责人: Lawrence C Brody
• 金额: $ 179.73万
• 依托单位: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7734875
• 关键词: Abruptio Placentae; Affect; Aging; Anemia; Area; Biological Assay; Blood; Brain; Child; Congenital Abnormality; Congenital Heart Defects; DNA Methylation; DNA Sequence; Data; Development; Diet; Disease; Elderly; Environmental Exposure; Family; Folate; Folic Acid Deficiency; Frequencies; Genes; Genetic Predisposition to Disease; Genetic Variation; Genome; Genotype; Goals; Health; Health Policy; Heart Diseases; Homocysteine; Homocystine; Human; Individual; Inherited; Knowledge; Laboratories; Link; Malignant Neoplasms; Maps; Measures; Metabolic; Metabolic Pathway; Metabolism; Methionine; Methylation; Molecular; Mothers; Neural Tube Defects; Neurologic; Numbers; Nutrient; Nutritional; Outcome; Pathogenesis; Pathway interactions; Phenotype; Population; Pregnancy; Pregnant Women; Public Health; Range; Research; Resolution; Risk; Risk Factors; Role; Sampling; Second Pregnancy Trimester; Series; Single Nucleotide Polymorphism; Site; Spinal Dysraphism; Spontaneous abortion; Staging; Supplementation; Symptoms; System; Testing; Tissues; Transcobalamins; Validation; Variant; Vitamin B 12; Vitamin B 12 Deficiency; cell growth; folic acid metabolism; gene function; genetic variant; protein function; research study; tumor

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 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. Early in 2008 we have tested more than 64 additional 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. This was carried out by genotyping more than 1,200 single nucleotide polymorphisms in a large number of families affected with neural tube defects and unaffected controls. This large experiment has allowed us to exclude most of the genes on this list. Results for approximately a dozen genes suggest that they are associated with neural tube defects. We have carried out second series of experiments to determine if the genes identified in the first stage of these are definitively associated with neural tube defects. These data are currently being analyzed. One of these genes has already passed through our stage 2 validation. This gene produces a protein that binds vitamin B12 and transports from the blood into the tissues. Our new data data that suggest that several variants in this transporter are associated with a risk of having a child with an NTD. While we now know which variants are associated with risk, we do not yet know if they are actually causing the risk or are linked to additional variants that change the function of the protein. To screen for additional variants, we sequenced the DNA containing this transporter gene in a large number of individuals. This sequencing experiment uncovered an number of previously unidentified variants in this gene. We are currently measuring the impact of these variants on the function of the transporter. We tested to see if one of these variants is associated with changes in vitamin B12 metabolism. We found that in young health individuals, the variant does not impact metabolic levels of vitamin B12. When we perform the same test in pregnant women, the variant is associated with decreased levels of vitamin B12. This result is consistent with the association of the same variant and adverse outcomes in pregnancy. We have also carried out experiment aimed at determining 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 used this assay on a large number of unrelated individuals and discovered that there is a wide range of methylation in healthy individuals. We are begiing to map methylation sites in the genome at high resolution. A detailed knowledge of the function of the the genes in the folatevitamin B12 metabolic pathways willadd to our understanding of neural tube defects and potentially help guide public health policy in the area of nutritional supplementation.

分子发病机理中的研究集中在定义基因的变化，这些基因是遗传性疾病（例如癌症和先天缺陷）的敏感性的基因的变化。叶酸代谢的变化是相关的肿瘤形成和先天缺陷。叶酸基因也参与了DNA的甲基化和适当的脑功能。 。我们正在寻找与叶酸，蛋氨酸和同型半胱氨酸代谢有关的基因中的遗传变异。将对患有癌症或脊柱裂（一种形式的神经管缺陷）的个体进行这些变体的测试。疾病个体中较高频率发现的变体将有助于我们识别与风险相关的基因。 过去，我们发现这些基因之一TC2中的一种变体似乎会影响怀孕期间血液中维生素B12的水平。这一发现可能与先天缺陷有关，也可能有助于解释为什么一些老年人贫血并遭受维生素B12缺乏症的神经系统症状。我们还发现，在第二个基因MTHFD1中携带特定变体的母亲的风险增加了50％，使儿童患有神经管缺陷。以前未描述的变体可能导致所有神经管缺陷的25％。人口中约有五分之一的人携带这些危险因素之一。我们最近确定，这种特殊的变体也是胎盘破裂的危险因素，这是流产的常见原因和在妊娠中期发生的siss虫。我们已经在实验室重新创建了这些基因，目前正在使用实验系统来确定这些变体如何改变这些蛋白质的功能。 在2008年初，我们已经测试了可能会扰动叶酸代谢的变体的64多个基因，因此与患有神经管缺陷的孩子的风险增加有关。这是通过在许多受神经管缺陷和未受影响控制的家庭中对大量家庭中的1,200多个单核苷酸多态性进行基因分型进行的。 这个大型实验使我们能够排除此列表中的大多数基因。大约十二个基因的结果表明它们与神经管缺陷有关。 我们已经进行了第二系列实验，以确定在第一阶段鉴定的基因是否与神经管缺陷完全相关。 这些数据目前正在分析。 这些基因之一已经通过了我们的第二阶段验证。该基因产生一种结合维生素B12并从血液传输到组织的蛋白质。我们的新数据表明，该转运蛋白中的几种变体与生孩子患有NTD的风险有关。 虽然我们现在知道哪些变体与风险相关，但我们尚不知道它们实际上是在造成风险，还是与改变蛋白质功能的其他变体有关。 为了筛选其他变体，我们对大量个体中包含该转运蛋白基因的DNA进行了测序。 该测序实验发现了该基因中许多先前未识别的变体。 目前，我们正在测量这些变体对转运蛋白功能的影响。 我们测试了这些变体之一是否与维生素B12代谢的变化有关。 我们发现，在年轻的健康人群中，这种变体不会影响维生素B12的代谢水平。 当我们在孕妇进行相同的测试时，该变体与维生素B12水平降低有关。 该结果与妊娠中相同变体和不良后果的关联是一致的。 我们还进行了旨在确定叶酸，维生素B12和DNA甲基化之间关系的实验。关于DNA甲基化的个体差异知之甚少。我们开发了一种测定法，使我们能够通过进行DNA测序来测量甲基化程度。我们在许多无关的个体上使用了该测定法，发现健康个体中存在广泛的甲基化。我们开始以高分辨率绘制基因组中的甲基化位点。详细了解叶酸维生素B12代谢途径中的基因的功能Willadd对我们对神经管缺陷的理解，并可能有助于指导营养补充方面的公共卫生政策。