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

描述(申请人提供)：出生缺陷是全球婴儿死亡的主要原因之一，但初级预防措施有限。先天性心脏病，包括右侧和左侧梗阻性心脏缺陷(OHD)，是最严重和最致命的出生缺陷之一。在美国，每1000名活产儿中就有8人患有先天性心脏病，而1 其中四分之一是老人院。大多数对OHD的遗传学研究都集中在特定的生物途径上，而留下了绝大多数基因组的未被探索。因此，我们建议对OHD进行全基因组扫描，利用基于国际HapMap和1000基因组计划的最近可用的遗传工具。我们假设OHD与母亲和婴儿的遗传变异、拷贝数变异(CNV)和基因特有的DNA甲基化模式有关。对这项拟议的研究至关重要的是，我们可以获得数千份以前从国家出生缺陷预防研究(NBDPS)收集的DNA样本。NBDPS是美国有史以来对出生缺陷进行的最大规模的病例对照研究。它的样本是由统一的诊断标准定义的具有良好特征的以人群为基础的队列，并附有孕妇关于怀孕接触情况和生活方式因素的报告。在我们提议的项目的发现阶段，我们将使用Illumina Human Omni2.5-8珠芯片对参与阿肯色州、加利福尼亚州或爱荷华州NBDPS站点的1,000例病例-父母三联体和对照-母体二联体(总共5,000名受试者)中常见和罕见的单核苷酸多态(SNPs)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识别的1,536个SNP的作用，样本包括1,000个病例-父母三联体和1,000个对照-母体二联体(同样，总共5,000名受试者)，他们参与了其余五个NBDPS站点。在这些努力的同时，我们将使用Illumina Infinium Human Methylation450珠芯片比较250个OHD病例-母体双体和250个对照-母体双体(总共1000名受试者)之间的基因特异性甲基化情况。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学结果，并确定涉及OHDs病因学的新途径。通过我们的发现，我们将有助于更丰富地了解OHD的病因，为公共卫生和临床预防和治疗战略提供基础。 公共卫生相关性：先天性梗阻性心脏缺陷是最普遍和最严重的出生缺陷之一，影响所有活产的1%。大多数对CHD的研究集中在选定的候选途径上，而留下了大部分基因组未被探索。我们提出了一种遗传和表观遗传学方法，该方法将利用基于1000个基因组的最近可用的技术进步；因此，使我们拟议的研究结果对以证据为基础的公共卫生和临床干预措施预防和治疗先天性梗阻性心脏缺陷做出重大贡献。

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.