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

• 批准号: 8432062
• 负责人: Dhananjay Madhukar Vaidya
• 金额: $ 48.96万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8432062
• 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; Health; 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; caucasian American; 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; vascular bed

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.

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共病并发症相关。虽然已知动脉功能障碍在老年人中更大，但对于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老年时保持足够的血管功能知之甚少。我们认为遗传因素是过早血管功能障碍的主要先兆。我们将在来自约翰霍普金斯兄弟姐妹和家族心脏研究的家族中检验这一假设，该研究是一项从早发冠状动脉疾病（CAD）先证者中确定的家族研究。我们已经描述了2500多名年龄在21岁至78岁之间的两代亲属。所有人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志物的基线测量结果。所有受试者均对涉及血管功能的190个候选基因中的4783个单核苷酸多态性（SNP）进行了高通量基因分型，包括炎症、细胞信号传导、血管张力和血管结构。所有这些都通过NHLBI STAMPEED程序进行了密集的1，000，000个全基因组SNP扫描。我们建议研究1500名没有临床表现的动脉粥样硬化性血管疾病的参与者，以确定两种年龄相关的血管功能表型：（1）颈动脉僵硬度，和（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，独立于动脉粥样硬化的危险因素和炎症标志物水平。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中过早血管功能障碍和血管功能保留的表型相关。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多种族研究，以及白人的心脏病研究）。这项研究应该提供的信息，特别是在白色和非洲裔美国人的家庭与年龄相关的血管功能障碍的基因的作用，有一个已知的倾向过早冠状动脉疾病。

项目成果

The association of brachial artery diameter with noncalcified coronary plaque burden in apparently healthy individuals.

表面健康个体中肱动脉直径与非钙化冠状动脉斑块负荷的关系。

• DOI: 10.1097/mca.0000000000000034
• 发表时间: 2013
• 期刊: Coronary artery disease
• 影响因子: 1.8
• 作者: Vaidya,Dhananjay;Kral,BrianG;Yanek,LisaR;Moy,TarynF;Fishman,ElliotK;Becker,DianeM;Becker,LewisC
• 通讯作者: Becker,LewisC