GENECARD-Gene Identification in Early-Onset CAD

GENECARD-早发 CAD 中的基因识别

• 批准号: 6601396
• 负责人: Elizabeth R Hauser
• 金额: $ 64.35万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6601396
• 关键词: adolescence (12-20); biotechnology; clinical research; coronary disorder; disease /disorder onset; family genetics; gene environment interaction; gene expression; genetic markers; genetic screening; genetic susceptibility; genotype; high performance liquid chromatography; human middle age (35-64); human tissue; informatics; linkage disequilibriums; linkage mapping; polymerase chain reaction; single nucleotide polymorphism; statistics /biometry; young adult human (21-34)

DESCRIPTION (provided by applicant): Coronary artery disease is the single leading cause of death in the US. Coronary Artery disease (CAD) is also a leading cause of disability. Identification of genes increasing susceptibility to CAD would have far reaching public health impact from enhancing motivation to make behavioral and lifestyle changes in susceptible individuals to providing basic biological and clinical information about the development and treatment of CAD. CAD is a complex disease with clear genetic and environmental risk factors. Early onset (premature) coronary artery disease (EOCAD), defined as age of onset less than 50 years of age, is known to have a particularly strong genetic component. However the actual genes leading to this increased risk and to a basic understanding of CAD remain obscure. Our goal is to identify genes increasing susceptibility to early onset coronary disease in a large sample of nuclear families with at least two members with EOCAD defined on the basis of a myocardial infarction, surgical procedure, or functional test before the age of 50 in men or 55 in women. We have completed a genome screen for EOCAD using 395 microsatellite markers in 438 families collected by the GENECARD study, a collaborative study involving 6 clinical investigative sites, GlaxoSmithKline and the Duke Center for Human Genetics. We have identified 9 regions providing consistent evidence for linkage in these families. We will concentrate on a region encompassing chromosome 3q13-q22 providing strong and consistent evidence for linkage (MLS=2.3). We propose to perform follow-up genotyping of microsatellite markers in these regions in the original set of families and in an additional set of almost 400 families. Candidate genes in those regions as well as genes identified from expression analyses carried out in other projects will be analyzed using linkage and family-based association. Our efforts in identifying new markers, SNPs and candidate genes for the follow-up studies will be aided by bioinformatics analyses and tools. We strongly believe that a detailed study of genetic factors and gene-environment interactions is an essential step to identifying targeted preventive strategies and more effective treatments.

描述（由申请人提供）：冠状动脉疾病是美国唯一的主要死亡原因。冠状动脉疾病（CAD）也是导致残疾的主要原因。识别增加 CAD 易感性的基因将对公共健康产生深远的影响，从增强易感个体改变行为和生活方式的动机到提供有关 CAD 发展和治疗的基本生物学和临床信息。 CAD 是一种复杂的疾病，具有明确的遗传和环境危险因素。早发性冠状动脉疾病 (EOCAD) 定义为发病年龄小于 50 岁，已知其具有特别强的遗传因素。然而，导致这种风险增加的实际基因以及对 CAD 的基本了解仍然不清楚。我们的目标是在至少有两名成员患有 EOCAD 的大样本核心家庭中鉴定出增加对早发性冠心病的易感性的基因，而 EOCAD 是根据男性 50 岁之前或女性 55 岁之前的心肌梗死、外科手术或功能测试来定义的。我们使用 GENECARD 研究收集的 438 个家系中的 395 个微卫星标记完成了 EOCAD 基因组筛选，该研究是一项涉及 6 个临床研究中心、葛兰素史克和杜克人类遗传学中心的合作研究。我们已经确定了 9 个区域，为这些家族之间的联系提供了一致的证据。我们将重点关注包含染色体 3q13-q22 的区域，为连锁提供强有力且一致的证据 (MLS=2.3)。我们建议对原始家族和另外近 400 个家族中这些区域的微卫星标记进行后续基因分型。这些区域中的候选基因以及从其他项目中进行的表达分析中鉴定出的基因将使用连锁和基于家族的关联进行分析。我们为后续研究确定新标记、SNP 和候选基因的努力将得到生物信息学分析和工具的帮助。我们坚信，对遗传因素和基因与环境相互作用的详细研究是确定有针对性的预防策略和更有效的治疗方法的重要一步。