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: 8941478
• 负责人: James Mills
• 金额: $ 14.84万
• 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/8941478
• 关键词: 2p13; 2p16.1; 2q12; 4p15.1; 9q34; Accounting; Affect; Age; Alcohol consumption; Alcohols; Animals; Antigens; Architecture; Area; Bibliography; Biochemical; Biochemical Pathway; Biological; Biological Assay; Candidate Disease Gene; Case-Control Studies; Chemicals; Child; Chromosomes; Chromosomes, Human, Pair 2; Cleaved cell; Clinical; Collaborations; Complex; Complex Genetic Trait; Conceptions; Congenital Abnormality; Congenital Heart Defects; Congenital omphalocele; Contraceptive Usage; Data; Data Set; Disease; Down Syndrome; Environmental Risk Factor; Epidemiology; Epilepsy; Europe; Exhibits; Face; Factor VIII-Related Antigen; Ferritin; Folate; Folic Acid; Future; Gender; Gene Mutation; Generalized Epilepsy; Genes; Genetic; Genetic Determinism; Genetic Polymorphism; Genome; Genotype; Glycoproteins; Goals; Grouping; Health; Hemoglobin; Hemorrhage; Heritability; Human; Individual; Investigation; Ireland; Iron; MTHFR gene; Manuscripts; Measures; Meta-Analysis; Metabolic Pathway; Metabolism; Methods; Micronutrients; Myocardial Infarction; National Institute of Child Health and Human Development; Neural Tube Defects; Neurology; Oral; Oral Contraceptives; Paper; Parents; Partial Epilepsies; Pathway interactions; Plasma; Plasminogen; Population; Population Analysis; Population Control; Pregnancy; Pregnant Women; Preparation; Properdin; Publications; Publishing; Pyridoxal Phosphate; Reporting; Research; Research Personnel; Risk; Risk Factors; Sampling; Siblings; Signal Transduction; Single Nucleotide Polymorphism; Smoking; Stroke; Structure; Students; Supplementation; Testing; Thrombosis; Tryptophan; Variant; Vitamin B6; Woman; Work; base; cohort; college; disease classification; folic acid metabolism; follow-up; genetic analysis; genetic linkage analysis; genetic risk factor; genetic variant; genome wide association study; genome-wide; hemoglobin L; human data; improved; interest; offspring; oral cleft; outcome forecast; prevent; risk variant; trait; volunteer; von Willebrand Factor

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. On going work is examining pathways in health young students of Irish genetic background (the Trinity Student Study) with several goals. These include identifying genetic factors using genome wide association study data that influence these pathways and defining how environmental influences such as smoking, alcohol and the use of supplements change the biochemical milieu. 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%. Gene variants in the folate metabolic pathway (e.g., MTHFR rs1801133 (677 C > T) and MTHFD1 rs2236225 (R653Q)) have been found to increase NTD risk. We hypothesized that other micronutrients and genes contribute to NTD risk. We have continued to search for environmental factors that might be related to the risk for having a child with a NTD. Animal studies have found an association between low iron status and having offspring with NTDs but human data were lacking. We tested this hypothesis in a case control study using samples from 64 pregnant women carrying an NTD affected pregnancy and 207 women with unaffected pregnancies. In the two groups the case median ferritin was 16.9 micrograms/L and the hemoglobin was 12.4g/dL vs. 15.4 micrograms/dL and 12.3 g/dL in the controls. Thus, there was no significant difference between the groups in iron status. Furthermore, there was no difference in ferritin or hemoglobin status between any subtype of NTD and the control population. Therefore, giving women iron prior to conception may improve maternal iron status but is not likely to prevent NTDs. Future investigations will explore genetic factors that have been shown to affect micronutrients of interest in our quantitative traits genome wide assocation study. For example, we have measured tryptophan pathway chemical concentrations in the over 2500 student volunteers in the Trinity Student Study and have generated genome wide data on their genetic variants. These data sets have been merged to determine the most important genetic factors that influence the tryptophan pathway taking into account the effect of gender, alcohol, smoking and oral contraceptive use. The analysis is complete and a manuscript has been prepared. These results will inform our investigation of genetic factors that may be associated with neural tube defect risk. A similar investigation is underway looking at genetic and environmental factors that affect vitamin B6 (pyridoxal phosphate and related vitamers). The data have been analyzed and a manuscript is in preparation. This study also uses the healthy student population. The genome wide association data we have generated on these students has also led to fruitful collaborations with outside investigators to study other quantitative traits. In these collaborations investigators receive samples from our study population for analysis. They assay the samples for the metabolite of interest. We then examine the genome to see what genes influence concentrations of the metabolite of interest. Our collaboration to study von Willebrand factor has recently been published in Proc Natl Acad Sci U S A . The plasma glycoprotein von Willebrand factor (VWF) exhibits fivefold antigen level variation across the normal human population determined by both genetic and environmental factors. Low levels of VWF are associated with bleeding and elevated levels with increased risk for thrombosis, myocardial infarction, and stroke. To identify additional genetic determinants of VWF antigen levels and to minimize the impact of age and illness-related environmental factors, we performed genome-wide association analysis in two young and healthy cohorts (n = 1,152 and n = 2,310) and identified signals at ABO (P < 7.9E-139) and VWF (P < 5.5E-16), consistent with previous reports. Additionally, linkage analysis based on sibling structure within the cohorts, identified significant signals at chromosome 2q12-2p13 (LOD score 5.3) and at the ABO locus on chromosome 9q34 (LOD score 2.9) that explained 19.2% and 24.5% of the variance in VWF levels, respectively. Given its strong effect, the linkage region on chromosome 2 could harbor a potentially important determinant of bleeding and thrombosis risk. The absence of a chromosome 2 association signal in this or previous association studies suggests a causative gene harboring many genetic variants that are individually rare, but in aggregate common. These results raise the possibility that similar loci could explain a significant portion of the "missing heritability" for other complex genetic traits. We have finished a second collaboration examining plasminogen that has been accepted for publication and will be published soon. A third collaboration using normal data from the Trinity Student Study GWAS involved studying genetic risk factors for epilepsy in a large multinational investigation. The study, just published in Lancet Neurology,included 8696 cases and 26,157 controls in our analysis. Meta-analysis of the all-epilepsy cohort identified loci at 2q24.3 (p=8.71x10(-10)), implicating SCN1A, and at 4p15.1 (p=5.44x10(-9)), harbouring PCDH7, which encodes a protocadherin molecule not previously implicated in epilepsy. For the cohort of genetic generalised epilepsy, we noted a single signal at 2p16.1 (p=9.99x10(-9)), implicating VRK2 or FANCL. No single nucleotide polymorphism achieved genome-wide significance for focal epilepsy. This meta-analysis describes a new locus not previously implicated in epilepsy and provides further evidence about the genetic architecture of these disorders, with the ultimate aim of assisting in disease classification and prognosis. The data suggest that specific loci can act pleiotropically raising risk for epilepsy broadly, or can have effects limited to a specific epilepsy subtype. Future genetic analyses might benefit from both lumping (ie, grouping of epilepsy types together) or splitting (ie, analysis of specific clinical subtypes). Both Dr. Ruzong Fan and Dr. Aiyi Liu, research statisticians on our project, have used our work and data to identify important statistical research questions. Their major area is looking for more efficient and powerful methods to identify true associations in genome-wide investigations. This work has produced several important papers noted in the bibliography. These will be discussed by Dr. Fan and Dr. Liu in their reports.

流行病学分公司与爱尔兰都柏林的卫生研究委员会和三一学院合作进行了许多先天缺陷研究。这些研究的主要目的是确定叶酸和先天缺陷之间的关系。迄今为止研究的先天缺陷是神经管缺陷（NTD），口腔裂缝，先天性心脏缺陷，唐氏综合症和卵黄静脉。这些研究的重点是叶酸代谢区域的生化因子，以及与先天缺陷相关的叶酸相关基因的遗传突变。最近的工作已经扩展到包括与先天缺陷有关的生化途径。 在上班上，正在研究爱尔兰遗传背景（三位一体学生学习）的健康年轻学生的途径。 这些包括使用基因组广泛的关联研究数据来识别遗传因素，从而影响这些途径，并定义环境影响，例如吸烟，酒精和补充剂的使用如何改变生化环境。 神经管缺陷（NTD）是具有复杂起源的常见先天缺陷（在美国和欧洲的1000例怀孕），包括环境和遗传因素。较低的母体叶酸是一个良好的危险因素，孕产妇的周围叶酸补充剂可将NTD妊娠的发生减少50-70％。叶酸代谢途径中的基因变异（例如MTHFR RS1801133（677 C> T）和MTHFD1 RS2236225（R653Q））被发现增加了NTD风险。我们假设其他微量营养素和基因有助于NTD风险。 我们继续寻找可能与生育NTD的孩子有关的环境因素。 动物研究发现，低铁状态与后代与NTD之间存在关联，但缺乏人类数据。 我们在一项案例对照研究中使用了64名携带NTD影响妊娠的孕妇和207名未受影响怀孕的妇女的样本进行了检验。 在这两组中，中位铁蛋白中位数为16.9微克/L，血红蛋白为12.4g/dl，对照组中的15.4微克/DL和12.3 g/dl。 因此，两组之间的铁状态没有显着差异。 此外，NTD的任何亚型与对照人群之间的铁蛋白或血红蛋白状态没有差异。 因此，在受孕之前给女性铁可以提高母体铁的状态，但不可能预防NTD。 未来的研究将探索遗传因素，这些因素已被证明会影响我们的定量性状广泛的基因组广泛关联研究。 例如，我们已经在三位一体学生研究中测量了2500多名学生志愿者中的色氨酸途径化学浓度，并为其遗传变异产生了广泛的基因组数据。 这些数据集已合并为确定影响色氨酸途径的最重要遗传因素，这些因素考虑了性别，酒精，吸烟和口服避孕药的影响。分析已完成，并准备了手稿。这些结果将为我们对可能与神经管缺陷风险相关的遗传因素的调查提供信息。 正在进行类似的研究，研究影响维生素B6（吡啶还毒素和相关维生素）的遗传和环境因素。 已经分析了数据，并正在准备手稿。 这项研究还使用健康的学生人数。 我们在这些学生上产生的基因组广泛的关联数据也导致了与外部研究人员研究其他定量性状的富有成果的合作。 在这些合作中，研究人员从我们的研究人群中收到样本进行分析。 他们分析样品的代谢物。 然后，我们检查基因组，以查看哪些基因会影响感兴趣的代谢产物的浓度。 我们研究von Willebrand因素的合作最近发表在Proc Natl Acad Sci u a中。 血浆糖蛋白von Willebrand因子（VWF）在正常人种群中表现出五倍的抗原水平变化，这些变异由遗传和环境因素决定。低水平的VWF与出血和升高水平有关，血栓形成，心肌梗塞和中风的风险增加。为了鉴定VWF抗原水平的其他遗传决定因素，并最大程度地减少与年龄和疾病相关的环境因素的影响，我们在两个年轻和健康的队列中进行了全基因组的关联分析（n = 1,152和n = 2,310），并确定了ABO的信号（p <7.9e-139）和VWF（p <5.5e-5e-16），一致性一致。此外，基于同胞内的同胞结构的连锁分析，确定了染色体2q12-2p13（LOD得分5.3）和ABO基因座的显着信号，在染色体9q34（LOD分数2.9）上解释了19.2％和24.5％的VWF水平方差的19.2％和24.5％。鉴于其强大的作用，染色体上的连锁区域可能具有出血和血栓形成风险的潜在重要决定因素。在这项或以前的关联研究中，缺乏2染色体的关联信号表明，具有许多遗传变异的病因，这些遗传变异是个体罕见的，但总共共同。这些结果增加了类似基因座可以解释其他复杂遗传特征的“缺失遗传力”的可能性。 我们已经完成了第二次合作研究纤溶酶原，该纤溶酶原已被接受，并将很快出版。 使用来自三位一体学生研究的正常数据GWA的第三次合作涉及在大型跨国研究中研究癫痫的遗传危险因素。这项刚刚发表在柳叶刀神经病学上的研究包括8696例病例和26,157例对照。全癫痫队队的荟萃分析在2q24.3（p = 8.71x10（-10））中鉴定出基因座，与SCN1A有关，在4p15.1（p = 5.44x10（-9））中，含有PCDH7，该pcdh7含有pCDH7，该pcdh7含有以前与protocadherrin molecule note epilepse concodepse sodepse sodepssy concepsssssise。对于遗传广义癫痫的队列，我们​​注意到2p16.1（p = 9.99x10（-9））的单个信号，与vrk2或fancl有关。没有单个核苷酸多态性实现了局灶性癫痫的全基因组意义。这项荟萃分析描述了一个以前与癫痫有关的新基因座，并提供了有关这些疾病遗传结构的进一步证据，其最终目的是协助疾病分类和预后。数据表明，特定的基因座可以广泛地提高癫痫的风险，或者可能仅限于特定癫痫亚型的效果。未来的遗传分析可能会受益于结块（即癫痫类型的分组）或分裂（即，特定临床亚型的分析）。 Ruzong Fan博士和我们项目的研究统计学家Aiyi Liu博士都使用我们的工作和数据来确定重要的统计研究问题。 他们的主要领域是寻找更有效，更强大的方法来识别全基因组研究中的真正关联。 这项工作产生了参考书目中指出的几篇重要论文。 这些将由Fan博士和Liu博士在他们的报告中讨论。