MOLECULAR GENETIC EPIDEMIOLOGY OF THREE CARDIAC DEFECTS

三种心脏缺陷的分子遗传流行病学

• 批准号: 6565113
• 负责人: RONALD M LAUER
• 金额: $ 44.31万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-01-01 至 2002-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6565113
• 关键词: cardiovascular disorder epidemiology; child (0-11); clinical research; congenital heart septum defect; developmental genetics; echocardiography; family genetics; genetic markers; genetic polymorphism; genetic susceptibility; genotype; human subject; linkage mapping; molecular pathology; phenotype

(Adapted from the Applicant's Abstract) Congenital heart defects (CHDs) are thought to result from genetic and environmental factors that disturb cardiac embryogenesis. Because families with multiple members affected with atrial septal defects (ASDs) and atrioventricular canal defects (AVCDs) have been described, and the paramembranous ventricular septum is in part completed by the formation of the atrioventricular cushions, this project describes a genetic-epidemiologic study of ASDs, paramembranous ventricular septal defects (VSDs), and AVCDs. Three groups of subjects, each with surgically- or echocardiographically-confirmed diagnoses of ASDs, VSDs or AVCDs have been identified for study at the University of Iowa Hospitals and Clinics, and at Wolfson Children's Hospital in Jacksonville, Florida. A fourth group of older subjects with ASDs and their progeny will be studied at Iowa because of the reported high recurrence of heart disease in the offspring of subjects with ASDs. The strategy proposed calls upon the molecular genetic capacities available at the University of Iowa to carry out genome-wide searches for genetic loci involved in these defects. Several candidate regions have been identified for ASDs, VSDs and AVCDs. In addition, three well-recognized syndromes provide additional candidate regions - Down syndrome, Holt-Oram syndrome and 8p-syndrome. Parent-affected child trios will be genotyped for closely-spaced markers within these regions and linkage disequilibrium analysis will be used to narrow or exclude these candidate intervals. A genome-wide association study of the trios will employ a parsimonious technique in which DNA from cases with the same CHD phenotype will be pooled, and compared to the pooled DNA from their parents. Loci will be identified where the allele frequency distributions in the affected children and their parents are significantly different. When such loci are identified, a finer localization of the chromosomal area will be undertaken using a high-density set of short tandem repeat polymorphic markers that spans each of the candidate intervals. This study has the potential to identify new candidate loci which are risk factors for the development of congenital heart defects.

先天性心脏缺陷（CHD）被认为是由干扰心脏胚胎发生的遗传和环境因素引起的。 由于多个成员患有房间隔缺损（ASD）和房室管缺损（AVCD）的家庭已被描述，膜旁室间隔部分由房室垫的形成完成，因此本项目描述了ASD，膜旁室间隔缺损（VSD）和AVCD的遗传流行病学研究。 在爱荷华州大学医院和诊所以及佛罗里达杰克逊维尔的沃尔夫森儿童医院确定了三组受试者，每组受试者均经手术或超声心动图确诊为ASD、VSD或AVCD。 第四组患有ASD的老年受试者及其后代将在爱荷华州进行研究，因为据报道患有ASD的受试者的后代心脏病复发率较高。 这项策略的提出，要求在爱荷华州大学的分子遗传能力，进行基因组范围内的搜索，这些缺陷涉及的遗传位点。 已经确定了ASD、VSD和AVCD的几个候选区域。 此外，三个公认的综合征提供了额外的候选区域-唐氏综合征，霍尔特-奥拉姆综合征和8 p综合征。 受父母影响的儿童三人组将在这些区域内对紧密间隔的标记进行基因分型，并使用连锁不平衡分析缩小或排除这些候选间隔。 三人组的全基因组关联研究将采用一种简约的技术，将来自具有相同CHD表型的病例的DNA合并，并与来自其父母的合并DNA进行比较。 基因座将被确定在受影响的儿童和他们的父母中的等位基因频率分布是显着不同的。当这样的基因座被确定，一个更精细的定位的染色体区域将进行使用一组高密度的短串联重复多态性标记，跨越每个候选区间。 这项研究有可能确定新的候选基因座，这些基因座是先天性心脏病发生的危险因素。