Genomic/Epigenomic Factors and Non-Syndromic Congenital Heart Defect Risk

描述（由申请人提供）：出生缺陷是世界范围内婴儿死亡的主要原因之一，但一级预防有限。先天性心脏缺陷，包括右侧和左侧阻塞性心脏缺陷（OHD），是最严重和致命的出生缺陷之一。在美国，每1,000名活产婴儿中就有8名患有先天性心脏缺陷， 其中四分之一是OHD。大多数OHD的遗传学研究都集中在特定的生物学途径上，而绝大多数基因组都未被探索。因此，我们建议，全基因组扫描的OHD，利用最近可用的遗传工具的基础上国际HapMap和1000基因组计划。我们假设OHD与母婴遗传变异、拷贝数变异（CNVs）和基因特异性DNA甲基化模式相关。这项研究的关键是，我们可以从国家出生缺陷预防研究（NBDPS）中获得数千份以前收集的DNA样本。NBDPS是美国有史以来最大的出生缺陷病例对照研究。它的样本是一个由统一诊断标准定义的特征良好的基于人群的队列，其中有妊娠暴露和生活方式因素的母亲报告。在我们提出的项目的发现阶段，我们将使用Illumina HumanOmni2.5-8 BeadChip对参与阿肯色州、加州或爱荷华州NBDPS站点的1，000个病例-父母三联体和对照-母亲二联体（共5，000名受试者）中常见和罕见的单核苷酸多态性（SNP）和CNV进行基因分型。在验证阶段，我们将使用定制的GoldenGate SNP阵列来验证在发现阶段确定的1，536个SNP的作用，这些SNP在参与其余五个NBDPS站点的1，000个病例-父母三联体和1，000个对照-母亲二联体（再次，总共5，000名受试者）的样本中。在这些努力的同时，我们将使用Illumina Infinium HumanMethylation 450 BeadChip比较250例OHD病例-母体二联体与250例对照-母体二联体（共1，000例受试者）的基因特异性甲基化谱。我们的项目汇集了来自六个出生缺陷研究项目的专家科学家，以整合基因组和表观基因组研究结果，并确定参与OHD病因学的新途径。通过我们的发现，我们将有助于更深入地了解OHD的病因，为公共卫生和临床预防和治疗策略提供基础。 公共卫生相关性：先天性阻塞性心脏缺陷是最普遍和最严重的出生缺陷之一，约占所有活产婴儿的1%。大多数CHD的研究都集中在选定的候选途径上，而大部分基因组都没有被探索。我们提出了一种遗传和表观遗传方法，该方法将利用基于1000个基因组的最新技术进步;从而使我们的研究结果为基于证据的公共卫生和临床干预做出重大贡献，以预防和治疗先天性阻塞性心脏病。

DESCRIPTION (provided by applicant): Birth defects are among the leading causes of infant mortality worldwide, yet primary prevention is limited. Congenital heart defects, including right- and left-sided obstructive heart defects (OHDs), are among the most serious and lethal of birth defects. Congenital heart defects occur in 8 of every 1,000 live births in the United States, and a quarter of these are OHDs. Most genetic studies of OHDs have focused on specific biological pathways, leaving the vast majority of the genome unexplored. We propose, therefore, a genome-wide scan of OHDs, taking advantage of recently available genetic tools based on the International HapMap and 1000 Genomes projects. We hypothesize that OHDs are associated with maternal and infant genetic variants, copy number variants (CNVs), and gene-specific DNA methylation patterns. Crucial to the proposed study is our access to thousands of previously collected DNA samples from the National Birth Defects Prevention Study (NBDPS). The NBDPS is the largest case-control study of birth defects ever conducted in the United States. Its sample is a well-characterized population-based cohort defined by uniform diagnostic criteria, which has accompanying maternal reports of pregnancy exposures and lifestyle factors. In the discovery phase of our proposed project, we will use the Illumina HumanOmni2.5-8 BeadChip to genotype both common and rare single nucleotide polymorphisms (SNPs) and CNVs in 1,000 case-parental triads and control-maternal dyads (5,000 subjects total) who participated in the Arkansas, California, or Iowa NBDPS sites. In the validation phase, we will use a custom GoldenGate SNP array to validate the role of 1,536 SNPs identified in the discovery phase, in a sample of 1,000 case-parental triads and 1,000 control-maternal dyads (again, 5,000 subjects total) who participated in the five remaining NBDPS sites. In parallel to these efforts, we will compare gene-specific methylation profiles between 250 OHD case-maternal dyads to those of 250 control-maternal dyads (1,000 subjects total) using the Illumina Infinium HumanMethylation450 BeadChip. Our project brings together expert scientists from six birth defects research programs to integrate genomic and epigenomic findings and identify novel pathways involved in the etiology of OHDs. Through our discoveries, we will contribute to a substantially richer understanding of the etiology of OHDs, providing a foundation for public health and clinical prevention and treatment strategies. PUBLIC HEALTH RELEVANCE: Congenital obstructive heart defects are among the most prevalent and serious of birth defects, affecting about 1% of all live births. Most research studie of CHDs focus on selected candidate pathways, leaving most of the genome unexplored. We propose a genetic and epigenetic approach that will take advantage of recently available technological advances based on the 1000 Genomes; thereby, making our findings of the proposed study a significant contribution to evidence-based public health and clinical interventions to prevent and treat congenital obstructive heart defects.