NICHD Health Research Board Of Ireland Neural Tube Defects Study

NICHD 爱尔兰健康研究委员会神经管缺陷研究

• 批准号: 10266487
• 负责人: James Mills
• 金额: $ 0.93万
• 依托单位: EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
• 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/10266487
• 关键词: Affect; Area; Biochemical; Biochemical Pathway; Blood; Brain; Candidate Disease Gene; Collaborations; Complex; Congenital Abnormality; Congenital Heart Defects; Congenital omphalocele; DNA Sequence Alteration; Data; Dihydrofolate Reductase; Dose; Down Syndrome; Enzymes; Epidemiology; Epilepsy; Erythrocytes; Europe; Face; Family Study; Folic Acid; Future; Generalized Epilepsy; Genes; Genetic; Genetic Polymorphism; Genomics; Genotype; Goals; Health; Homocysteine; Individual; International; Investigation; Ireland; Measures; Metabolism; Methylation; Micronutrients; National Institute of Child Health and Human Development; Neural Tube Defects; Oral; Parents; Participant; Pathogenicity; Pathway interactions; Plasma; Population; Pregnancy; Reporting; Research; Resources; Risk Factors; Role; Sampling; Serum; Single Nucleotide Polymorphism; Testing; Tetrahydrofolates; Variant; Vitamin B 12; Vitamin B6; Vitamin B6 Metabolism Pathway; Vitamins; Work; base; college; dihydrofolate; early onset; epileptic encephalopathies; folic acid metabolism; folic acid supplementation; follow-up; genetic variant; genome wide association study; oral cleft; prevent; risk variant

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. Recent work has expanded to include the biochemical pathways related to birth defects. Neural tube defects (NTDs) are common birth defects (1 in 1000 pregnancies in the US and Europe) that have complex origins, including environmental and genetic factors. A low level of maternal folate is one well-established risk factor, with maternal periconceptional folic acid supplementation reducing the occurrence of NTD pregnancies by 50-70%. The role of folic acid is very well established in preventing NTDs. It is also known that genetic factors are important based on family studies. To date only a few genetic variants have been shown to be important. This research has been hindered by the lack of data on how genetic variants affect folate status in the population. We conducted both candidate gene analyses and genome wide association studies in 2232 young subjects from a genetically Irish background. We measured serum folate, red cell folate and total plasma homocysteine. Current work includes examining the role of another folate pathway gene, dihydrofolate reductase. The enzyme produced by this gene is critical in the conversion of folic acid, a synthetic form of folate, into the active form, tetrahydrofolate. It is also important in converting dihydrofolate to tetrahydrofolate in the normal folate pathway. Other ongoing work explores the relevance of variants in genes that affect vitamin B12, another important vitamin related to NTDs because of its role in methylation. Our genome wide association data have been used in numerous collaborations. Most recently they were part of a mega-analysis led by the International League Against Epilepsy Consortium on Complex Epilepsies. Altered vitamin B6 metabolism due to pathogenic variants in the gene PNPO causes early onset epileptic encephalopathy, which can be treated with high doses of vitamin B6. We recently reported that single nucleotide polymorphisms (SNPs) that influence PNPO expression in the brain are associated with genetic generalized epilepsy (GGE). However, it is not known whether any of these GGE-associated SNPs influence vitamin B6 metabolite levels. We found that 84 GGE-associated SNPs influence expression levels of PNPO in the brain as well as in blood. However, these SNPs were not associated with vitamin B6 metabolism in plasma. We anticipate continuing to explore genomic associations with NTDs and biochemical pathways in the future.

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。最近的工作已经扩大到包括与出生缺陷有关的生化途径。 神经管缺陷（NTD）是一种常见的出生缺陷（在美国和欧洲，每1000例妊娠中就有1例），其起源复杂，包括环境和遗传因素。母体叶酸水平低是一个公认的风险因素，母体围受孕期补充叶酸可将NTD妊娠的发生率降低50- 70%。 叶酸在预防NTD中的作用非常明确。 根据家族研究，遗传因素也很重要。 迄今为止，只有少数遗传变异被证明是重要的。 这项研究由于缺乏关于遗传变异如何影响人群中叶酸状态的数据而受到阻碍。 我们进行了候选基因分析和全基因组关联研究，在2232个年轻的受试者从遗传爱尔兰背景。 我们测定了血清叶酸，红细胞叶酸和血浆总同型半胱氨酸。 目前的工作包括研究另一个叶酸途径基因，二氢叶酸还原酶的作用。 由该基因产生的酶在叶酸（叶酸的合成形式）转化为活性形式四氢叶酸的过程中至关重要。 在正常叶酸途径中，它在将二氢叶酸转化为四氢叶酸中也很重要。 其他正在进行的工作探索了影响维生素B12的基因变异的相关性，维生素B12是另一种与NTD相关的重要维生素，因为它在甲基化中起作用。 我们的全基因组关联数据已被用于许多合作。 最近，他们参与了由国际抗癫痫联盟复杂癫痫联盟领导的大型分析。由于PNPO基因中的致病性变体导致的维生素B6代谢改变会导致早发性癫痫性脑病，可以用高剂量的维生素B6治疗。我们最近报道，单核苷酸多态性（SNPs），影响PNPO在大脑中的表达与遗传性全身性癫痫（GGE）。然而，目前尚不清楚这些GGE相关的SNP是否会影响维生素B6代谢物水平。我们发现，84个GGE相关的SNP影响PNPO在大脑和血液中的表达水平。然而，这些SNPs与血浆中维生素B6代谢无关。 我们期望在未来继续探索NTD和生化途径的基因组关联。