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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：
8150617
负责人：
Dhananjay Madhukar Vaidya
金额：
$ 77.75万
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 2013-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8150617
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

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.