Maternal Genes that Control Early Embryonic Development as Risk Factors for Congenital Heart Defects

控制早期胚胎发育的母体基因是先天性心脏病的危险因素

基本信息

批准号：
9982092
负责人：
LAURA E. MITCHELL
金额：
$ 23.86万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-20 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9982092
关键词：
Adult Affect Animals Automobile Driving Biological Birth CHD7 gene Cardiac Categories Child Cohort Studies Complex Congenital Abnormality Congenital Heart Defects Counseling Data Data Analyses Data Set Development Echocardiography Embryo Embryonic Development Embryonic Heart Epidemiology Funding Genes Genetic Genetic study Genome Genotype Goals Heart Abnormalities High Risk Woman Human Individual Infant Infant Mortality Inherited Investigation Knowledge Left Lesion Letters Life Mammals Minority Morbidity - disease rate Oocytes Parents Pediatric Cardiac Genomics Consortium Pediatric Hospitals Philadelphia Population Prenatal care Prevalence Prevention approach Prevention strategy Proteins Public Health Research Risk Risk Factors Role Side Specificity Structural Congenital Anomalies Syndrome Teratogens Transcript Translating United States Woman base cardiogenesis conotruncal heart defect epidemiology study fetal gene product genetic variant genome wide association study improved improved outcome insight knockout gene maternal diabetes mortality non-genetic novel offspring population based prevent reproductive screening screening panel secondary analysis statistics

项目摘要

Project Summary/Abstract With a birth prevalence of approximately 1/100, congenital heart defects (CHDs) are the most common birth defects and the leading cause of birth defect related infant mortality. CHDs cannot be cured and there are no population-based prevention strategies. Further, the specific causes of most CHDs are unknown. The gaps in our understanding of the causes of CHDs hamper our ability to prevent CHDs. Hence, the long-term goal of our research is to identify the causes of CHDs and to use this knowledge to develop CHD prevention strategies. To this end, we conducted a gene-level, genome-wide association study of conotruncal heart defects (CTDs) and the maternal genotype. The results of this study suggest the novel hypothesis that the maternal genotype influences embryonic heart development via maternal gene products present in the oocyte that direct early embryonic development. Maternal genes that affect embryonic development in this way are called maternal effect genes (MEGs). In our study, there was a 2-3 fold enrichment of mammalian MEGs among the maternal genes that were most significantly associated with CTDs (p<0.05). Our objective in this proposal is to identify the specific MEGs, and the variants within these MEGs, that are associated with CTDs. Specifically, our working hypothesis for the proposed studies is that maternal genotypes for a subset of MEGs are associated with the risk of CTDs and these associations extend to other types of CHDs, specifically left-sided cardiac lesions (LSLs). We will achieve our aims through secondary analyses of data from three large, independent, study cohorts: 1465 case-parent trios (670 CTD1; 478 CTD2; 317 LSLs) from the Children’s Hospital of Philadelphia; and 547 trios (355 CTDs, 192 LSLs) from the Pediatric Cardiac Genomics Consortium. In Aim 1, we will identify the specific MEGs, and the variants within these MEGs, that are driving the observed MEG enrichment. In Aim 2, we will evaluate MEGs in LSLs, to establish the specificity of MEG-CTD associations. In summary, our preliminary data provide support for a novel hypothesis about the role of the maternal genotype in the development of CHDs in offspring. Confirmation of this hypothesis would provide new insight into the causes of CHDs and, perhaps, other structural birth defects. Hence, the studies proposed in this application have the potential to significantly affect the fields of birth defect epidemiology and genetics, as well as public health efforts to prevent birth defects.

项目摘要/摘要出生率约为1/100，先天性心脏缺陷（CHD）是最常见的出生缺陷和出生缺陷相关的婴儿死亡率的主要原因。 CHD无法治愈，没有基于人群的预防策略。此外，大多数CHD的具体原因是未知的。差距我们对CHD的原因的理解阻碍了我们预防CHD的能力。因此，我们的长期目标研究是为了确定CHD的原因，并利用这些知识来制定CHD预防策略。到这一目的，我们进行了一项基因级，全基因组心脏缺陷（CTD）和母体基因型。这项研究的结果表明了母体基因型的新假设通过存在于卵母细胞中的材料基因产物来影响胚胎心脏的发育胚胎发展。以这种方式影响胚胎发育的母体基因称为母体效应基因（MEGS）。在我们的研究中，孕产妇中有2-3倍的哺乳动物Megs 与CTD最显着相关的基因（p <0.05）。我们在此提案中的目标是确定与CTD相关的特定MEG和这些MEG中的变体。具体来说，我们的工作提出的研究的假设是，MEGS子集的母体基因型与 CTD和这些关联的风险扩展到其他类型的CHD，特别是左侧心脏病变（LSL）。我们将通过对三个大型，独立的研究队列的数据进行二次分析来实现我们的目标：1465 来自费城儿童医院的案例父母三重奏（670 CTD1; 478 CTD2; 317 LSLS）；和547三重奏（355个CTD，192 LSL）来自小儿心脏基因组学联盟。在AIM 1中，我们将确定特定的 MEGS以及这些MEGS中的变体都推动了观察到的MEG富集。在AIM 2中，我们将评估LSLS中的MEGS，以建立MEG-CTD关联的特异性。总之，我们的初步数据提供有关母体基因型在CHD发展中的作用的新假设的支持后代。确认这一假设将为CHD的原因提供新的见解，也许是其他的结构性先天缺陷。因此，本应用中提出的研究有可能显着影响出生缺陷流行病学和遗传学领域，以及公共卫生为预防出生缺陷而努力。