Molecular Determinants of Coronary Artery Disease

描述(申请人提供)：在西方世界，最重要的死亡和残疾原因是动脉粥样硬化性冠状动脉疾病(CAD)及其主要并发症-急性心肌梗死(MI)。该项目的长期目标是确定冠心病和心肌梗死的遗传途径和分子机制。这一建议的中心假设是，CAD/MI的发病机制涉及关键基因的功能突变，这些突变扰乱了CAD/MI所涉及的复杂分子过程。为此，最近，在一个常染色体显性遗传CAD/MI的大型家系中，我们发现了一个特殊的MEF2A突变(21个碱基缺失)，似乎与该家族的CAD/MI(科学，出版中)有关。此外，我们已经完成了对CAD/MI易感基因的全基因组扫描，该队列由428个早产儿CAD和MI(平均发病年龄：44.4±9.7岁)多胎家庭的1163名患者组成。在检测到与染色体区域连锁的8个新的显著MI易感基因座中，Lp34-36显示多点等位基因共享P值为&lt；10-12(LOD=11.68)。目前的提议是由这些令人兴奋的结果推动的。具体目标是：特定目标1：利用单个大家族和基于模型的连锁分析和定位克隆，定位和鉴定一个新的CAD/MI基因。首先，我们将继续通过鉴定MEF2A基因敲除小鼠和转基因小鼠与CAD/MI相关的表型来验证我们的发现，即MEF2A基因突变导致家族性CAD/MI。设计了一系列分子和细胞生物学实验，以探索MEF2A缺失的分子机制。我们还将确定MEF2A中的SNPs，并通过关联研究确定其中一些SNPs是否会增加或降低常见复杂CAD/MI的风险。其次，我们计划继续使用基于模型的连锁分析和位置克隆来定位和鉴定至少一个新的CAD/MI基因。我们招募了三个与MEF2A无关的大型扩展CAD/MI家系，每个家系在统计学上都有足够的能力(模拟的LOD分数分别为3.53、7.22和6.62)来进行与CAD和MI显著连锁的全基因组扫描。此外，在这项研究中，已经确定了16个受影响个人超过4人的家庭，每个家庭平均有27个在世的兄弟姐妹和父母。具体目标2：为了确定染色体区域lp34-36上的MI易感基因，我们将重点放在染色体lp34-36区域的MI基因座上，因为这是迄今为止发现的与MI最显著的连锁(LOD评分为11.68)。我们将进行精细定位、候选基因的鉴定、SNP鉴定和基因分型_家族-TDT分析(同胞关系不平衡检验)以及基于人群的病例对照研究，以确定候选基因中的特定SNP或SNP单倍型是否与MI相关。这项建议中研究目标的实现有可能对了解CAD和MI的分子机制产生重大影响，从而促进更好的预防、诊断和治疗。

DESCRIPTION (provided by applicant): The most important cause of death and disability in the Western world is atherosclerotic coronary artery disease (CAD) and its primary complication-acute myocardial infarction (MI). The long-term objective of this project is to define genetic pathways and molecular mechanisms for CAD and MI. The central hypothesis of this proposal is that the pathogenesis of CAD/MI involves functional mutations in key genes that perturb the complex molecular processes involved in CAD/MI. To this end, recently, in a large pedigree with autosomal dominant CAD/MI, we identified a specific MEF2A mutation (21-bp deletion) that appears to be responsible for this family's CAD/MI (Science, in press). Furthermore, we have completed a genomewide scan for susceptibility genes for CAD/MI in a well characterized U.S. cohort consisting of 1,163 affected persons in 428 multiplex families with premature CAD and MI (average age at onset: 44.4 + 9.7 years). Of eight novel significant susceptibility loci detected for MI linkage to the chromosomal region lp34-36 showed multipoint allelesharing P values of <10 -12 (LOD = 11.68). The present proposal is driven by these exciting results. The specific aims are: Specific Aim 1: To map and identify a novel CAD/MI gene using single large families and model-based linkage analysis, and positional cloning. First, we will continue to validate our finding that mutations in MEF2A cause familial CAD/MI by characterizing the MEF2A knockout mice and transgenic mice for phenotype related to CAD/MI. A series of molecular and cell biological experiments are designed to explore the molecular mechanisms of the MEF2A deletion. We will also identify SNPs in MEF2A and determine whether some of the SNPs increase or decrease the risk of common complex CAD/MI by association studies. Secondly, we plan to continue to use model-based linkage analysis and positional cloning to map and identify at least one new CAD/MI gene. We have recruited three large and extended CAD/MI pedigrees that are not linked toMEF2A, and each family has statistically sufficient power (simulated LOD scores of 3.53, 7.22, and 6.62, respectively) to conduct a genomewide scan of significant linkage to CAD and MI. Furthermore, 16 families of more than four affected individuals have been identified with an average of 27 living siblings and parents per family for this study. Specific Aim 2: To identify the susceptibility gene for MI on the chromosomal region lp34-36, We will focus on the chromosome lp34-36 MI locus for our follow-up gene discovery effort because this is the most significant linkage identified for MI to date (LOD score of 11.68). We will perform fine mapping, identification of candidate genes, SNP identification and genotyping_ family-TDT analysis (Sibship Disequilibrium Test) as well as population-based case-control studies to determine whether a specific SNP or SNP haplotype in a candidate gene is associated with MI. The accomplishment of research objectives in this proposal has the potential to have a substantial impact on the understanding of the molecular mechanism of CAD and MI, thereby facilitating better prevention, diagnosis and therapy.