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: 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
• 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

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 (&#8804;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一些出生缺陷研究。这些研究的主要目的是确定叶酸与出生缺陷之间的关系。到目前为止，研究的出生缺陷包括神经管缺陷(NTDS)、口腔裂、先天性心脏缺陷、唐氏综合症和脐膨出。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。在过去，我们已经证明，升高的同型半胱氨酸是NTDS的危险因素，亚甲基四氢叶酸还原酶(MTHFR)基因677C-gt；T的突变是NTDS的危险因素，小剂量的叶酸(100-200微克)可以将红细胞叶酸提高到可以预防五分之一到近一半NTDS的水平。我们已经证明，亚甲基四氢叶酸还原酶(MTHFD)是NTDS的危险因素，MTHFD是合成DNA所需的嘌呤和嘧啶的重要基因。我们已经证明，叶酸受体的自身抗体，以前被认为是NTDS的重要危险因素，在受影响的妊娠中并不比未受影响的妊娠更常见。我们已经报道，维生素B12水平不足或接近正常范围的妇女更有可能生出患有NTDS的孩子。 最近，我们扩大了对母亲叶酸状况和出生缺陷风险之间可能关系的调查，测量了怀有非神经管缺陷畸形的胎儿的血浆叶酸和维生素B12水平。携带有任何出生缺陷(神经管缺陷除外)的受影响胎儿的母亲，其母亲的叶酸和B12水平并没有显著降低。令人惊讶的是，在两个病例组：腭裂和肌肉骨骼缺陷的母亲中，B12水平明显更高。这可能是一个偶然的发现，但需要进行额外的调查。 为了确定NTDS的遗传风险因素，我们评估了潜在的功能性单核苷酸多态(SNPs)，这些SNPs是NTDS的生物学可信的危险因素，但从未被研究过与NTDS的关联，检查了已发表的研究中未显示与NTDS相关的SNPs，并试图确认先前报道的叶酸相关和非叶酸相关基因的关联。我们在爱尔兰的558个病例家庭(520个病例，507个母亲，457个父亲)和994个对照中，研究了与脊柱裂相关的34个基因的SNPs。采用病例对照和母体对照比较、传递不平衡检验和对数线性回归模型计算效应估计。脊柱裂与LEPR(瘦素受体)rs1805134次要C等位基因和COMT(儿茶酚-O-甲基转移酶)rs737865主要T等位基因的过度传递相关，与先前的报道一致，脊柱裂与MTHFR 677C和GT；T(短臂)rs3127334，LEPR K109R和PDGFRA启动子单倍型组合相关。LEPR SNPs与脊柱裂之间的关联提示了肥胖是NTD危险因素这一发现的可能机制。COMT变异与脊柱裂之间的关联可能涉及甲基化和表观遗传学。 我们的全基因组关联研究数据使我们能够解决与叶酸强化食品有关的一个重要的公共卫生问题。几项针对老年人的研究发现，那些血液叶酸水平高而维生素B12水平低的人有更严重的B12问题，包括贫血和B12新陈代谢的改变。在我们的横断面研究中，2507名大学生提供了有关病史和接触叶酸和维生素B-12补充剂的数据。采血检测血清及血清中红细胞叶酸(RCF)、血球蛋白、血浆同型半胱氨酸(THcy)、甲基丙二酸(MMA)、转钴胺和铁蛋白。在维生素B-12浓度较低的受试者(148pmol/L)中，叶酸浓度较高的受试者(组1)与叶酸浓度较低的受试者(组2)相比，在任何区域的维生素B-12细胞功能的异常程度都不明显。与组2相比，组1的全转钴胺和RCF值显著升高，总同型半胱氨酸显著降低，MMA浓度无显著差异(P=0.057)。两组在血红蛋白和铁蛋白方面无显著差异。与第2组相比，第1组从补充剂和强化食品中摄取的叶酸和维生素B-12的平均摄入量显著增加。在这个年轻的成年人群中，高叶酸浓度并没有加剧与维生素B-12缺乏相关的生化异常。这些结果保证了强化食品和补充剂中的叶酸不会干扰健康人群细胞水平上的维生素B-12代谢。