Genetic Determinants of Premature Vascular Dysfunction in Families

描述(申请人提供)：动脉功能障碍，以血管僵硬和内皮损伤为特征，与包括动脉粥样硬化在内的共病并发症有关。尽管已知动脉功能障碍在老年人更严重，但人们对为什么一些人在相对年轻的时候表现出血管功能障碍，而另一些人在相对较大的年龄保持足够的血管功能的原因知之甚少。我们认为遗传因素是早产儿血管功能障碍的主要先兆之一。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，这是一项研究，研究的家庭是从先证者中识别出的早发冠状动脉疾病(CAD)。我们已经描述了2500多名两代人的亲属，现在年龄在21岁到78岁之间。所有患者都有动脉粥样硬化危险因素、伴随的生活方式和炎症生物标记物的基线测量。所有受试者都高通量地对190个候选基因中的4783个单核苷酸多态(SNPs)进行了基因分型，这些基因与血管功能有关，包括炎症、细胞信号、血管张力和血管结构。所有人现在都通过NHLBI STAMPEED计划进行了密集的100万全基因组SNP扫描，进行了完全的基因分型。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。我们将独立于动脉粥样硬化和炎症标记物水平的风险因素，确定候选基因的多态与早产儿血管功能障碍的关联程度。此外，我们还将检查全基因组SNP扫描中哪些新的遗传位点与老年受试者早产血管功能障碍和保留的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动脉粥样硬化的多种族研究，以及白人的弗雷明翰心脏研究)。这项研究应该提供与基因在白人和非裔美国人家庭中与年龄相关的血管功能障碍的具体相关信息，这些家庭有早发冠状动脉疾病的已知倾向。

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.