Genetic Determinants of Premature Vascular Dysfunction in Families

家庭早发性血管功能障碍的遗传决定因素

基本信息

批准号：
7860577
负责人：
Dhananjay Madhukar Vaidya
金额：
$ 70.17万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2011-12-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7860577
关键词：
21 year old Accounting Adult Children African American Age Age-Years Animals Arteries Atherosclerosis Biological Markers Biological Preservation Biological Process Blood Pressure Blood Vessels Body mass index CCL2 gene Candidate Disease Gene Cardiovascular system Carotid Arteries Chronic Coronary Arteriosclerosis Coronary heart disease Databases Dilatation - action Disease Enrollment Epidemiology Family Family Study Family member Framingham Heart Study Functional disorder General Population Genes Genetic Genetic Determinism Genetic Models Genetic Polymorphism Genotype Glucose Goals Haplotypes Heart Heart failure Human Impairment Individual Inflammation Inflammatory Influentials Interleukin-6 Lead Life Style Lipids Measurement Measures Mediating Morbidity - disease rate Myocardial Infarction National Heart, Lung, and Blood Institute Obesity Parents Participant Persons Phenotype Population Population Study Predisposition Process Property Recording of previous events Relative (related person)Research Design Risk Factors Role Scanning Siblings Signal Transduction Single Nucleotide Polymorphism Structure Susceptibility Gene Testing Variant Vascular Diseases age group age related base brachial artery density disorder risk early onset gene discovery genetic profiling genetic variant genome wide association study genome-wide high risk inflammatory marker mortality novel offspring population based premature primary outcome proband programs public health relevance vascular bed

项目摘要

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.

描述（由申请人提供）：以血管硬化和内皮损伤为特征的动脉功能障碍与包括动脉粥样硬化在内的共病并发症相关。尽管已知动脉功能障碍在年龄较大时更为严重，但人们对为什么有些人在相对年轻时表现出血管损伤而另一些人在相对较年长时仍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过早血管功能障碍的主要先兆之一。我们将在约翰·霍普金斯大学兄弟姐妹和家庭心脏研究的家庭中检验这一假设，该研究是对患有早发冠状动脉疾病 (CAD) 的先证者进行的家庭研究。我们对 2500 多名两代亲属进行了特征分析，年龄在 21 岁至 78 岁之间。所有这些都对动脉粥样硬化危险因素、随之而来的生活方式和炎症生物标志物进行了基线测量。所有受试者均对涉及血管功能（包括炎症、细胞信号传导、血管张力和血管结构）的 190 个候选基因的 4783 个单核苷酸多态性 (SNP) 进行了高通量基因分型。现在，所有这些都已通过 NHLBI STAMPEED 计划进行了密集的 1,000,000 个全基因组 SNP 扫描，进行了完全基因分型。我们计划对 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，以及（2）缺血后肱动脉血流介导的扩张。我们将确定候选基因的多态性与过早血管功能障碍的相关程度，与动脉粥样硬化和炎症标志物水平的危险因素无关。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受试者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复制我们的发现（针对白人和非裔美国人的动脉粥样硬化多种族研究，以及针对白人的弗雷明汉心脏研究）。这项研究应该提供与基因在已知有早发冠状动脉疾病倾向的白人和非裔美国家庭中与年龄相关的血管功能障碍中的作用相关的信息。公众健康相关性：慢性炎症被认为会过早地使动脉变得僵硬和功能不良，从而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有早发冠心病史的家族中已知的和新发现的基因有关。我们的结果将帮助我们了解哪些基因和机制导致过早动脉疾病。