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

基本信息

批准号：
8351158
负责人：
James Mills
金额：
$ 50万
依托单位：
EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
依托单位国家：
美国
项目类别：
财政年份：
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/8351158
关键词：
Address Affect Alleles Anemia Antibodies Area Biochemical Blood Brachyury protein Candidate Disease Gene Catechol O-Methyltransferase Cell physiology Cleaved cell Cleft Palate Collaborations Congenital Abnormality Congenital Heart Defects Congenital omphalocele Cross-Sectional Studies DNA biosynthesis Data Defect Dose Down Syndrome Elderly Epidemiology Epigenetic Process Erythrocytes Exposure to Face Family Fathers Ferritin Fetus Folate Folic Acid Food Food Supplements Fortified Food Frequencies Gene Mutation Genes Genetic Genetic Polymorphism Genotype Goals Haplotypes Health Hemoglobin Homocysteine Homocystine Individual Intake Investigation Ireland Linear Regressions Measures Medical History Metabolism Methylation Methylenetetrahydrofolate reductase (NADPH)Methylmalonic Acid Micronutrients Minor Modeling Mothers Musculoskeletal Mutation National Institute of Child Health and Human Development Neural Tube Defects Obesity Oral PDGFRA gene Parents Plasma Population Pregnancy Production Public Health Publishing Purines Pyrimidine Reporting Research Risk Risk Factors Sampling Serum Single Nucleotide Polymorphism Spinal Dysraphism Testing Tube Ursidae Family Variant Vitamin B 12 Vitamin B 12 Deficiency Woman case control college folate-binding protein folic acid metabolism follow-up fortification genetic risk factor genetic variant genome wide association study leptin receptor malformation oral cleft prevent promoter purine transmission process university student young adult

项目摘要

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. In the past we have shown that elevated homocysteine is a risk factor for NTDs, that a mutation in the methylenetetrahydrofolate reductase (MTHFR) gene 677C->T is a risk factor for NTDs, and that a small dose of folic acid (100-200 micrograms) can raise red cell folate to levels that can prevent a fifth to almost a half of NTDs. We have shown that methylenetetrahydrofolate reductase (MTHFD), an important gene in the production of purine and pyrimidine for DNA synthesis, is a risk factor for NTDs. We have shown that auto-antibodies to the folate receptor, previously considered to be an important risk factor for NTDs, are no more common in affected pregnancies than unaffected pregnancies. We have reported that women with vitamin B12 levels in the deficient or borderline range are significantly more likely to bear childrene with NTDs. We have recently expanded our investigation of the possible relationship between maternal folate status and birth defect risks by measuring plasma folate and vitamin B12 levels in women carrying a fetus with a non-neural tube defect malformation. Maternal folate and B12 levels were not significantly lower in mothers carrying affected fetuses for any of the birth defects (other than neural tube defects). Surprisingly, B12 levels were significantly higher in mothers of two case groups: cleft palate and musculoskeletal defects. This may be a chance finding but requires additional investigation. To identify genetic risk factors for NTDs, we evaluated potentially functional single nucleotide polymorphisms (SNPs) that are biologically plausible risk factors for NTDs but that have never been investigated for an association with NTDs, examined SNPs that previously showed no association with NTDs in published studies, and tried to confirm previously reported associations in folate-related and non-folate-related genes. We investigated 64 SNPs in 34 genes for association with spina bifida in up to 558 case families (520 cases, 507 mothers, 457 fathers) and 994 controls in Ireland. Case-control and mother-control comparisons of genotype frequencies, tests of transmission disequilibrium, and log-linear regression models were used to calculate effect estimates. Spina bifida was associated with over-transmission of the LEPR (leptin receptor) rs1805134 minor C allele and the COMT (catechol-O-methyltransferase) rs737865 major T allele Consistent with previous reports, spina bifida was associated with MTHFR 677C>T, T (Brachyury) rs3127334, LEPR K109R, and PDGFRA promoter haplotype combinations. The associations between LEPR SNPs and spina bifida suggest a possible mechanism for the finding that obesity is a NTD risk factor. The association between a variant in COMT and spina bifida implicates methylation and epigenetics as possible mechanisms. Our genome wide association study data enabled us to address an important public health issue regarding food fortification with folic acid. Several studies of elderly individuals found that those who had high blood folate levels in conjunction with low vitamin B12 status had more severe B12 problems including anemia and alterations of B12 metabolism. In our cross-sectional study, 2507 university students provided data on medical history and exposure to folic acid and vitamin B-12 supplements. Blood was collected to measure serum and red blood cell folate (RCF), hemoglobiin, plasma homocysteine (tHcy), methylmalonic acid (MMA), holootranscobalamin, and ferritin in serum. In subjects with low vitamin B-12 concentrations (<148 pmol/L), those who had high folate concentrations (>30 nmol/L; group 1) did not show greater abnormalities in vitamin B-12 cellular function in any area than did those with lower folate concentrations (≤30 nmol/L; group 2). Group 1 had significantly higher holotranscobalamin and RCF, significantly lower tHcy, and nonsignificantly lower (P = 0.057) MMA concentrations than did group 2. The groups did not differ significantly in hemoglobin or ferritin. Compared with group 2, group 1 had significantly higher mean intakes of folic acid and vitamin B-12 from supplements and fortified food. In this young adult population, high folate concentrations did not exacerbate the biochemical abnormalities related to vitamin B-12 deficiency. These results provide reassurance that folic acid in fortified foods and supplements does not interfere with vitamin B-12 metabolism at the cellular level in a healthy population.

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。过去，我们已经表明，同型半胱氨酸的升高是NTD的危险因素，甲基苯二甲酸酯叶酸还原酶（MTHFR）基因677C-> t是NTD的危险因素，而一小剂量的叶酸（100-200微克）可以将红细胞（100-200微克）提高到五分之一的水平。我们已经表明，甲基苯甲酸叶酸还原酶（MTHFD）是嘌呤和嘧啶用于DNA合成的重要基因，是NTD的危险因素。我们已经表明，叶酸受体的自身抗体（以前被认为是NTD的重要危险因素）在受影响的妊娠中并不比未受影响的怀孕更常见。我们报道说，缺乏或边界范围内维生素B12水平的女性更有可能与NTD相关。最近，我们通过测量携带具有非神经管缺陷畸形的胎儿的女性中血浆叶酸和维生素B12水平来扩大对母体叶酸状况和先天缺陷风险之间可能关系的研究。在任何出生缺陷（神经管缺陷之外），母亲的母体叶酸和B12水平并未显着降低。令人惊讶的是，两个病例组的母亲的B12水平明显更高：left裂和肌肉骨骼缺陷。这可能是一个机会，但需要进行额外的调查。为了鉴定NTD的遗传危险因素，我们评估了潜在的功能性单核苷酸多态性（SNP），这些核苷酸多态性（SNP）是NTD的生物学上可行的风险因素，但从未研究过与NTD相关联的研究，这些SNP与先前在已发表的研究中没有与NTD相关联的SNP，并试图证实与先前报道的与先前报告的合作和非元素相关联，并依赖于基因依赖的基因。我们调查了34个基因中的64个SNP，以与脊柱裂相关，最多558个病例家族（520例，507个母亲，457个父亲）和994个对照在爱尔兰。基因型频率，传输不平衡测试以及对数线性回归模型的病例对照和母体比较用于计算效应估计值。脊柱裂与LEPR（瘦素受体）rs1805134较小的C等位基因和COMT（Catechol-O-O-甲基转移酶）RS737865主要T等位基因与先前的报告一致，MTHFR 677C> T，T，T，T，T，T，T，t，t，brifida与先前的报告相关联PDGFRA启动子单倍型组合。 LEPR SNP和脊柱裂之间的关联提出了一种发现肥胖是NTD危险因素的可能机制。 COMT和脊柱裂之间的变体之间的关联意味着甲基化和表观遗传学作为可能的机制。我们的基因组广泛协会的研究数据使我们能够解决有关叶酸食品强化的重要公共卫生问题。对老年人的几项研究发现，与维生素B12状态低的血叶酸水平高的人患有更严重的B12问题，包括贫血和B12代谢的改变。在我们的横断面研究中，有2507名大学生提供了有关病史以及暴露于叶酸和维生素B-12补充剂的数据。收集血液以测量血清和红细胞叶酸（RCF），血红蛋白，血浆同型半胱氨酸（THCY），甲基丙二酸（MMA），Holootranscobalamin和Serum中的铁蛋白。在维生素B-12浓度低（<148 pmol/L）的受试者中，叶酸浓度高的受试者（> 30 nmol/L;组1）在任何区域的维生素B-12细胞功能中没有比叶酸浓度较低（≤30nmol/l;组2）在任何区域的异常异常。第1组的Holotranscobalamin和RCF明显更高，THCY明显降低，而MMA浓度低（P = 0.057）的含量低于第2组。在血红蛋白或铁蛋白中，组没有显着差异。与第2组相比，第1组的叶酸和维生素B-12的平均摄入量明显更高。在这个年轻人人群中，高叶酸浓度不会加剧与维生素B-12缺乏有关的生化异常。这些结果可以放心，在健康人群中，强化食品和补充剂中的叶酸不会干扰细胞水平的维生素B-12代谢。