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: 10459125
• 负责人: James Mills
• 金额: $ 0.97万
• 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/10459125
• 关键词: Address; Affect; Allergic; Area; Biochemical; Biochemical Pathway; Biochemistry; Biological Markers; Blood; Brain; Candidate Disease Gene; Carbon; Collaborations; Complex; Congenital Abnormality; Congenital Heart Defects; Congenital omphalocele; DNA Sequence Alteration; Data; Dihydrofolate Reductase; Dose; Down Syndrome; Enzymes; Epidemiology; Epilepsy; Erythrocytes; Europe; Family Study; Folic Acid; Food; Future; Generalized Epilepsy; Genes; Genetic; Genetic Polymorphism; Genomics; Genotype; Goals; Health; Homocysteine; Individual; International; Investigation; Ireland; Label; Measures; Metabolism; Micronutrients; National Institute of Child Health and Human Development; Neural Tube Defects; Parents; Participant; Pathogenicity; Pathway interactions; Plasma; Population; Pregnancy; Public Health; Published Comment; Publishing; Quantitative Trait Loci; Reporting; Research; Research Personnel; Resources; Risk Factors; Role; Sampling; Serum; Signal Transduction; Single Nucleotide Polymorphism; Testing; Tetrahydrofolates; Tissues; Variant; Vitamin B6; Vitamin B6 Metabolism Pathway; Work; base; cohort; college; dihydrofolate; early onset; epileptic encephalopathies; folic acid metabolism; folic acid supplementation; follow-up; fortification; genetic variant; genome wide association study; mRNA Expression; 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. Our investigation, recently published, revealed mixed results. We observed an association with NTDs signal in an Irish cohort but failed to replicate this in a separate, smaller UK cohort. We also assessed DHFR2 as a potential QTL for biomarkers of folate one carbon metabolism and as a eQTL. Upon correction for multiple tests, these analyses did not show any significant correlations with serum folate, red cell folate, plasma total homocysteine, plasma formate, or tissue mRNA expression levels. Thus, the role of DHFR2 remains to be determined. 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. Our work on folate has expanded into areas beyond biochemistry and genetics. We recently collaborated on a commentary discussing the possible role of unmetabolized folic acid in allergic conditions. We also collaborated in an investigation of folic acid labeling, suggesting ways to make it clearer and more consistent with RDA data. We anticipate continuing to explore genomic associations with NTDs and biochemical pathways in the future.

流行病学分部正在与健康研究委员会和爱尔兰都柏林三一学院合作进行多项出生缺陷研究。这些研究的主要目的是确定叶酸与出生缺陷之间的关系。迄今为止研究的出生缺陷包括神经管缺陷（NTD）、口腔裂、先天性心脏病、唐氏综合症和脐膨出。这些研究重点关注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。最近的工作已扩展到包括与出生缺陷相关的生化途径。 神经管缺陷 (NTD) 是常见的出生缺陷（在美国和欧洲，千分之一的妊娠就有这种缺陷），其起源复杂，包括环境和遗传因素。母体叶酸水平低是一项公认的危险因素，母体围孕期补充叶酸可将 NTD 妊娠的发生率降低 50-70%。 叶酸在预防 NTD 方面的作用已得到充分证实。 根据家庭研究还知道遗传因素很重要。 迄今为止，只有少数遗传变异被证明是重要的。 由于缺乏关于遗传变异如何影响人群叶酸状态的数据，这项研究受到阻碍。 我们对 2232 名具有爱尔兰遗传背景的年轻受试者进行了候选基因分析和全基因组关联研究。 我们测量了血清叶酸、红细胞叶酸和总血浆同型半胱氨酸。 目前的工作包括检查另一种叶酸途径基因二氢叶酸还原酶的作用。 该基因产生的酶对于将叶酸（叶酸的合成形式）转化为活性形式四氢叶酸至关重要。 它对于正常叶酸途径中二氢叶酸转化为四氢叶酸也很重要。我们最近发表的调查显示了好坏参半的结果。我们在爱尔兰队列中观察到与被忽视的热带疾病信号的关联，但未能在另一个较小的英国队列中复制这种关联。我们还评估了 DHFR2 作为叶酸一碳代谢生物标志物的潜在 QTL 和 eQTL。经过多次测试校正后，这些分析没有显示出与血清叶酸、红细胞叶酸、血浆总同型半胱氨酸、血浆甲酸盐或组织 mRNA 表达水平的任何显着相关性。因此，DHFR2 的作用仍有待确定。 我们的全基因组关联数据已用于众多合作中。 最近，他们参与了由国际抗癫痫联盟联盟领导的复杂癫痫大型分析。 PNPO 基因致病性变异导致维生素 B6 代谢改变，导致早发性癫痫性脑病，可用高剂量维生素 B6 治疗。我们最近报道，影响大脑中 PNPO 表达的单核苷酸多态性 (SNP) 与遗传性全面性癫痫 (GGE) 相关。然而，尚不清楚这些 GGE 相关 SNP 是否会影响维生素 B6 代谢水平。我们发现 84 个 GGE 相关 SNP 影响大脑和血液中 PNPO 的表达水平。然而，这些 SNP 与血浆中维生素 B6 代谢无关。 我们对叶酸的研究已扩展到生物化学和遗传学以外的领域。 我们最近合作撰写了一篇评论，讨论未代谢叶酸在过敏性疾病中的可能作用。 我们还合作进行了叶酸标签的调查，提出了使其更清晰、与 RDA 数据更一致的方法。 我们预计未来将继续探索基因组与 NTD 和生化途径的关联。