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: 10687742
• 负责人: James Mills
• 金额: $ 2.09万
• 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/10687742
• 关键词: Address; Adverse effects; Affect; Allergic; Allergic Disease; Anaphylaxis; Area; Basic Science; Biochemical; Biochemical Pathway; Biochemistry; Biological; Blood; Brain; Candidate Disease Gene; Carbon; Cells; Child; Collaborations; Complex; Congenital Abnormality; Congenital Heart Defects; Congenital omphalocele; DNA Methylation; DNA Sequence Alteration; Data; Data Analyses; Development; Distress; Dose; Down Syndrome; Epidemiology; Epilepsy; Erythrocytes; Etiology; Europe; Exposure to; Family Study; Folic Acid; Food; Future; Gene Expression; Generalized Epilepsy; Genes; Genetic; Genetic Polymorphism; Genomics; Genotype; Goals; Health; Homocysteine; Hypersensitivity; Individual; Intake; International; Investigation; Ireland; Life; Measures; Metabolism; Micronutrients; National Institute of Child Health and Human Development; Neural Tube Defects; Neurodevelopmental Disorder; Outcome; Parents; Participant; Pathogenicity; Pathway interactions; Plasma; Population; Pregnancy; Public Health; Published Comment; Reaction; Reporting; Research; Research Personnel; Resources; Risk; Risk Factors; Role; Sampling; Serum; Single Nucleotide Polymorphism; Skin; Source; Testing; Variant; Vitamin B6; Vitamin B6 Metabolism Pathway; Woman; Work; autism spectrum disorder; base; college; early onset; editorial; epileptic encephalopathies; folic acid metabolism; folic acid supplementation; follow-up; fortification; genetic variant; genome wide association study; histone methylation; infancy; methyl group; offspring; oral cleft; prenatal; 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. 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. Reviewing the evidence, we concluded that the data fail a critical test for causality. The mix of positive and negative studies fails the consistency test. The findings are not specific to any outcome, although this is not critical. The findings, far from being strong, include beneficial as well as harmful effects of prenatal FA exposure. In summary, allergic disease in infancy comprises a heterogeneous group of skin and airway conditions that range from uncomfortable and distressing both for the children and their parents to life-threatening anaphylaxis. FA exposure in pregnancy is not an important factor contributing to the reported increase in allergies. We also wrote a recent editorial analyzing the data suggesting an association between maternal folic acid intake and offspring autism spectrum disorder (ASD). Many studies have explored the influence of maternal folic acid (FA) intake on the risk of ASD in their offspring. There are 2 reasons to think that folate could be important in preventing ASD. First, maternal FA supplementation in the periconceptional period protects against the occurrence of neural tube defects, which are also neurodevelopmental disorders. Second, 1-carbon units derived from folate pathways are the main source of methyl groups for essential DNA and histone methylation reactions. Inadequate availability of such methyl groups could potentially affect gene expression, as suggested in studies exploring folate-related risk factors for ASD. In fact, most reports find that FA protects against ASD. We concluded that normal doses of FA have been shown to have a beneficial effect on development. A biological mechanism for an adverse effect has not been persuasively demonstrated, but the effect of UMFA inside the cell is largely unknown. Overall, the 2 studies on UMFA to date are contradictory, which speaks against a serious harmful effect, but the studies have serious limitations. Future investigations should focus on women exposed to high doses of FA during pregnancy and on the basic science of UMFA at the cellular level. 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。 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。 我们对叶酸的研究已经扩展到生物化学和遗传学之外的领域。 我们最近合作了一篇评论，讨论了未代谢的叶酸在过敏性疾病中的可能作用。回顾证据，我们得出结论，数据未能通过因果关系的关键检验。阳性和阴性研究的混合未能通过一致性检验。这些发现并不针对任何结果，尽管这并不重要。这些发现，远远不是强有力的，包括产前FA暴露的有益和有害影响。总之，婴儿期过敏性疾病包括一组异质性皮肤和气道疾病，其范围从儿童及其父母的不适和痛苦到危及生命的过敏反应。怀孕期间暴露于FA并不是导致报告的过敏增加的重要因素。 我们最近还写了一篇社论，分析了母亲叶酸摄入量与后代自闭症谱系障碍（ASD）之间的关联。许多研究探讨了母亲叶酸（FA）摄入量对其后代ASD风险的影响。有两个理由认为叶酸在预防ASD中可能很重要。首先，在围受孕期母体补充FA可以防止神经管缺陷的发生，这也是神经发育障碍。第二，叶酸途径的1-碳单元是必需DNA和组蛋白甲基化反应的甲基的主要来源。这些甲基的可用性不足可能会影响基因表达，正如探索ASD的叶酸相关风险因素的研究所建议的那样。事实上，大多数报告发现FA可以预防ASD。我们的结论是，正常剂量的FA已被证明对发育有有益的影响。不良反应的生物学机制尚未得到令人信服的证明，但UMFA在细胞内的作用在很大程度上是未知的。总的来说，迄今为止关于UMFA的两项研究是矛盾的，这与严重的有害影响相反，但这些研究有严重的局限性。未来的调查应集中在妇女在怀孕期间暴露于高剂量的FA和UMFA在细胞水平上的基础科学。 我们期望在未来继续探索NTD和生化途径的基因组关联。

项目成果

Is low iron status a risk factor for neural tube defects?

• DOI: 10.1002/bdra.23223
• 发表时间: 2014-02
• 期刊: BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY
• 作者: Molloy, Anne M.;Einri, Caitriona Nic;Jain, Divyanshu;Laird, Eamon;Fan, Ruzong;Wang, Yifan;Scott, John M.;Shane, Barry;Brody, Lawrence C.;Kirke, Peadar N.;Mills, James L.
• 通讯作者: Mills, James L.

The FUT2 secretor variant p.Trp154Ter influences serum vitamin B12 concentration via holo-haptocorrin, but not holo-transcobalamin, and is associated with haptocorrin glycosylation.

FUT2 分泌变体 p.Trp154Ter 通过 Holo-haptocorrin（而非 Holo-转钴胺素）影响血清维生素 B12 浓度，并且与 haptocorrin 糖基化相关。

• DOI: 10.1093/hmg/ddx369
• 发表时间: 2017
• 期刊: Human molecular genetics
• 影响因子: 3.5
• 作者: Velkova,Aneliya;Diaz,JenniferEL;Pangilinan,Faith;Molloy,AnneM;Mills,JamesL;Shane,Barry;Sanchez,Erica;Cunningham,Conal;McNulty,Helene;Cropp,CherylD;Bailey-Wilson,JoanE;Wilson,AlexanderF;Brody,LawrenceC
• 通讯作者: Brody,LawrenceC

Lowering the risk of autism spectrum disorder with folic acid: can there be too much of a good thing?

用叶酸降低自闭症谱系障碍的风险：好事会太多吗？

• DOI: 10.1093/ajcn/nqac048
• 发表时间: 2022
• 期刊: The American journal of clinical nutrition
• 作者: Mills,JamesL;Molloy,AnneM
• 通讯作者: Molloy,AnneM

Serum unmetabolized folic acid in a nationally representative sample of adults ≥60 years in the United States, 2001-2002.

• DOI: 10.3402/fnr.v56i0.5616
• 发表时间: 2012
• 期刊: Food & nutrition research
• 影响因子: 3.3
• 作者: Bailey RL;Mills JL;Yetley EA;Gahche JJ;Pfeiffer CM;Dwyer JT;Dodd KW;Sempos CT;Betz JM;Picciano MF
• 通讯作者: Picciano MF

Fortifying food with folic acid to prevent neural tube defects: are we now where we ought to be?

用叶酸强化食物以预防神经管缺陷：我们现在达到了我们应该达到的水平吗？

• DOI: 10.1093/ajcn/nqy110
• 发表时间: 2018
• 期刊: The American journal of clinical nutrition
• 作者: Molloy,AnneM;Mills,JamesL
• 通讯作者: Mills,JamesL