Genetic Determinants of Premature Vascular Dysfunction in Families

描述（由申请人提供）：动脉功能障碍，以血管硬化和内皮损伤为特征，与包括动脉粥样硬化在内的合并症并发症相关。虽然已知动脉功能障碍在老年时更严重，但很少有人知道为什么有些人在相对年轻时就表现出血管损伤，而另一些人在相对年老时仍保持足够的血管功能。我们认为遗传因素是早期血管功能障碍的主要前驱之一。我们将在约翰霍普金斯兄弟姐妹和家庭心脏研究的家庭中检验这一假设，这是一项从先证者中确定患有过早冠状动脉疾病（CAD）的家庭的研究。我们对2500多名两代同堂的亲戚进行了分析，他们的年龄在21岁到78岁之间。所有人都有动脉粥样硬化危险因素、相关生活方式和炎症生物标志物的基线测量。所有受试者都对190个候选基因的4783个单核苷酸多态性（SNPs）进行了高通量基因分型，这些基因涉及血管功能，包括炎症、细胞信号、血管张力和血管结构。通过NHLBI STAMPEED程序进行密集的1,000,000个全基因组SNP扫描，现在所有人都完全基因分型。我们建议对1500名没有临床表现的动脉粥样硬化性血管疾病的参与者进行研究，以确定两种与年龄相关的血管功能表型(1)颈动脉僵硬，(2)缺血后肱动脉血流介导的扩张。我们将确定候选基因多态性与过早血管功能障碍相关的程度，独立于动脉粥样硬化和炎症标志物水平的危险因素。此外，我们还将研究全基因组SNP扫描中哪些新的遗传位点与老年人过早血管功能障碍和保留血管功能的表型相关。我们将在两项基于人群的研究中重复我们的发现（白人和非裔美国人的多种族动脉粥样硬化研究和白人的弗雷明汉心脏研究）。这项研究应该提供基因在白人和非裔美国人家族中与年龄相关的血管功能障碍中的作用，这些家庭已知有过早冠状动脉疾病的倾向。公共卫生相关性：慢性炎症被认为会过早地使动脉硬化和功能不良，导致心脏病发作和心力衰竭。我们正在测试这些疾病过程是否与已知和新发现的有早发冠心病史的家族基因有关。我们的研究结果将帮助我们了解哪些基因和机制导致过早的动脉疾病。

DESCRIPTION (provided by applicant): Arterial dysfunction, characterized by vascular stiffening and endothelial impairment, is associated with co-morbid complications including atherosclerosis. Though arterial dysfunction is known to be greater at older ages, little is known about why some individuals manifest vascular impairment when relatively young and others retain adequate vascular function at relatively older ages. We propose that genetic factors are among the primary precursors of premature vascular dysfunction. We will examine this hypothesis in families from the Johns Hopkins Sibling and Family Heart Study, a study of families identified from a proband with premature coronary artery disease (CAD). We have characterized over 2500 two-generational relatives, now aged 21 to 78 years. All have baseline measurements of atherosclerosis risk factors, attendant lifestyles, and inflammatory biomarkers. All subjects have had high throughput genotyping of 4783 single nucleotide polymorphisms (SNPs) in 190 candidate genes involved in vascular function, including inflammation, cell signaling, vascular tone, and vascular structure. All are now fully genotyped with a dense 1,000,000 genome wide SNP scan through the NHLBI STAMPEED program. We propose to study 1500 participants without clinically manifest atherosclerotic vascular disease to determine two age-related vascular function phenotypes (1) carotid artery stiffness, and (2) post-ischemic brachial artery flow-mediated dilatation. We will determine the extent to which polymorphisms in candidate genes are associated with premature vascular dysfunction, independent of risk factors for atherosclerosis and inflammatory marker levels. Further, we will also examine which novel genetic loci in the genome wide SNP scan are associated with the phenotypes of premature vascular dysfunction and preserved vascular function in older subjects. We will replicate our findings in two population-based studies (the Multi-Ethnic Study of Atherosclerosis for whites and African Americans, and the Framingham Heart Study for whites). This study should provide information specifically related to the role of genes in age-related vascular dysfunction in white and African American families with a known propensity toward premature coronary artery disease. PUBLIC HEALTH RELEVANCE: Chronic inflammation is thought to prematurely make arteries stiffer and function poorly, leading to heart attacks and heart failure. We are testing whether these disease processes are associated with known and newly discovered genes in families with history of premature coronary diseases. Our results will help us understand what genes and mechanisms lead to premature artery diseases.