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: 8553895
• 负责人: James Mills
• 金额: $ 40.77万
• 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/8553895
• 关键词: Affect; Alleles; Area; Biochemical; Brachyury protein; CDKN2A gene; Candidate Disease Gene; Catechol O-Methyltransferase; Cleaved cell; Collaborations; Complex; Confidence Intervals; Congenital Abnormality; Congenital Heart Defects; Congenital omphalocele; Data; Data Set; Down Syndrome; Epidemiology; Epigenetic Process; Erythrocytes; Europe; Evaluation; Face; Family; Fathers; Folate; Folic Acid; Fortified Food; Frequencies; Future; Gene Mutation; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genotype; Goals; Haplotypes; Health; Individual; Investigation; Ireland; Joints; Linear Regressions; MTHFR gene; Measures; Metabolic Pathway; Metabolism; Methylation; Micronutrients; Minor; Modeling; Mothers; National Institute of Child Health and Human Development; Neural Tube Defects; Obesity; Oral; PDGFRA gene; Parents; Pathway interactions; Pregnancy; Publishing; Relative Risks; Reporting; Research; Risk; Risk Factors; Sample Size; Sampling; Serum; Signal Transduction; Single Nucleotide Polymorphism; Spinal Dysraphism; Students; Supplementation; Testing; Triad Acrylic Resin; Variant; base; case control; college; folic acid metabolism; follow-up; genetic association; genetic risk factor; genetic variant; genome wide association study; genome-wide; interest; leptin receptor; mouse model; oral cleft; promoter; trait; transmission process; volunteer

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. Individual studies of the genetics of neural tube defects (NTDs) contain results on a small number of genes in each report. 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 genotype relative risk (GRR): 1.5; 95% confidence interval (CI): 1.0-2.1; P&#8201;=&#8201;0.0264 and the COMT (catechol-O-methyltransferase) rs737865 major T allele (GRR: 1.4; 95% CI: 1.1-2.0; P&#8201;=&#8201;0.0206). After correcting for multiple comparisons, these individual test P-values exceeded 0.05. 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 in NTDs. 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 variants in additional folate/B12 pathway genes contribute to NTD risk. A tagSNP approach was used to screen common variation in 82 candidate genes selected from the folate/B12 pathway and NTD mouse models. We initially genotyped polymorphisms in 320 Irish triads (NTD cases and their parents), including 301 cases and 341 Irish controls to perform case-control and family based association tests. Significantly associated polymorphisms were genotyped in a secondary set of 250 families that included 229 cases and 658 controls. The combined results for 1441 SNPs were used in a joint analysis to test for case and maternal effects. Nearly 70 SNPs in 30 genes were found to be associated with NTDs at the p < 0.01 level. The ten strongest association signals (p-value range: 0.0003-0.0023) were found in nine genes (MFTC, CDKN2A, ADA, PEMT, CUBN, GART, DNMT3A, MTHFD1 and T (Brachyury)) and included the known NTD risk factor MTHFD1 R653Q (rs2236225). The single strongest signal was observed in a new candidate, MFTC rs17803441 (OR = 1.61 1.23-2.08, p = 0.0003 for the minor allele). Though nominally significant, these associations did not remain significant after correction for multiple hypothesis testing. To our knowledge, with respect to sample size and scope of evaluation of candidate polymorphisms, this is the largest NTD genetic association study reported to date. The scale of the study and the stringency of correction are likely to have contributed to real associations failing to survive correction. We have produced a ranked list of variants with the strongest association signals. Variants in the highest rank of associations are likely to include true associations and should be high priority candidates for further study of NTD risk. 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 serum and red cell folate levels in over 2500 student volunteers and have generated genome wide data on their genetic variants. These data sets will be merged to determine the most important genetic factors that influence folate levels controlling for use of folic acid containing supplements and fortified food. These results will inform our investigation of genetic factors that are associated with neural tube defect risk.

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。 对神经管缺陷(NTD)遗传学的个别研究在每一份报告中都包含了针对少量基因的结果。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等位基因相对危险度：1.5；95%可信区间：1.0-2.1；P=0.0264；和COMT(儿茶酚-O-甲基转移酶)rs737865主要T等位基因(相对危险度：1.4；95%CI：1.1-2.0；P&8201；0.0206)的过度传播有关。在对多次比较进行校正后，这些单项测试的P值超过0.05。与以前的报道一致，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变异和脊柱裂之间的关联涉及NTDS的甲基化和表观遗传学。 神经管缺陷(NTD)是一种常见的出生缺陷(美国和欧洲每1000例孕妇中就有一例)，其原因复杂，包括环境和遗传因素。低水平的母亲叶酸是一个公认的危险因素，母亲孕周补充叶酸可将NTD妊娠的发生率降低50%-70%。叶酸代谢途径中的基因变异(例如，MTHFR rs1801133(677 C&gt；T)和MTHFD1 rs2236225(R653Q))已被发现增加NTD的风险。我们假设额外的叶酸/B12途径基因变异会增加NTD的风险。 采用TagSNP方法筛选了叶酸/B12途径和NTD小鼠模型中82个候选基因的共同变异。我们最初对320名爱尔兰三联症患者(NTD患者及其父母)进行了基因分型，其中包括301名患者和341名爱尔兰对照，以进行病例对照和基于家庭的关联检验。在包括229个病例和658个对照在内的250个家系中，对显著相关的基因多态进行了分型。1441个SNPs的综合结果被用于联合分析，以检验病例和母亲的影响。 在P&lt；0.01水平上，30个基因中的近70个SNP被发现与NTDS相关。在9个基因(MFTC、CDKN2A、ADA、PEMT、CUBN、GART、DNMT3A、MTHFD1和T(Brachyury))中发现了10个最强的关联信号(p值范围为0.0003-0.0023)，其中包括已知的NTD风险因子MTHFD1R653Q(Rs2236225)。在新的候选基因MFTC rs17803441中观察到单一最强的信号(OR=1.611.23-2.08，p=0.0003)。虽然名义上显著，但在对多重假设检验进行校正后，这些相关性并不显著。 据我们所知，就样本大小和候选多态的评估范围而言，这是迄今为止报道的最大的NTD基因关联研究。这项研究的规模和纠正的严格性很可能是导致真正的关联未能幸免于纠正的原因之一。我们已经制作了一份具有最强关联信号的变体排名列表。关联度最高的变种很可能包括真实关联性，应该是进一步研究非传染性疾病风险的高优先级候选者。 未来的研究将探索在我们的数量性状全基因组关联研究中已被证明影响感兴趣的微量营养素的遗传因素。例如，我们测量了2500多名学生志愿者的血清和红细胞叶酸水平，并生成了关于他们遗传变异的全基因组数据。这些数据集将被合并，以确定影响叶酸水平的最重要的遗传因素，以控制含有叶酸的补充剂和强化食品的使用。这些结果将为我们研究与神经管缺陷风险相关的遗传因素提供信息。