NOVEL FACTORS FOR UNEXPLAINED PHENOTYPES OF SUBCLINICAL CAROTID ATHEROSCLEROSIS

亚临床颈动脉粥样硬化无法解释的表型的新因素

基本信息

批准号：
8672699
负责人：
SUSAN HALLORAN BLANTON
金额：
$ 32.47万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8672699
关键词：
Abbreviations Alleles Area Atherosclerosis Blood Vessels Cardiovascular Diseases Cardiovascular system Caribbean region Carotid Arteries Carotid Artery Plaques Carotid Atherosclerotic Disease Cause of Death Cessation of life Cholesterol Homeostasis Clinical Common carotid artery Communities Complex Copy Number Polymorphism DNA Repository Data Development Diabetes Mellitus Diet Disease Outcome Dyslipidemias Environmental Risk Factor Etiology Evaluation Studies External carotid artery structure Family Family Study Genes Genetic Genetic Determinism Genetic Polymorphism Genomics Genotype Gray unit of radiation dose Guidelines Health Heritability Hispanics Human Hypertension Image Image Analysis Individual Inflammatory Institutes Internal carotid artery structure Ischemic Stroke Lead Lipids Measures Modeling Molds Myocardial Infarction Neurology Phenotype Population Process Protocols documentation Quantitative Trait Loci Regulation Research Residual state Resources Risk Risk Factors Sample Size Sampling Sampling Studies Scanning Short Tandem Repeat Side Signal Transduction Single Nucleotide Polymorphism Smoking Smooth Muscle Staging Stroke System Text Thick Ultrasonography Validation Variant Vascular Diseases base clinical phenotype cohort disability experience follow-up genetic analysis genetic association genome wide association study innovation intima media novel population based therapeutic target trait uptake

项目摘要

DESCRIPTION (provided by applicant): Precursor conditions or subclinical markers provide an opportunity to understand the early determinants of atherosclerosis. Traditional vascular risk factors predict less than a half of variance in carotid plaque and a half of individuals experience plaque progression despite treatment of traditional vascular risk factors according to current guidelines. Individuals with progression of subclinical atherosclerosis have twice the risk of stroke, myocardial infarction or death over 5 years, compared to those with stable plaque or regression. Atherosclerosis is a complex condition with a substantial genetic contribution. Specific genetic polymorphisms involved in regulation of subclinical carotid atherosclerosis and their extreme unexplained phenotypes are not known. A search for new alleles that either accelerate or protect from atherosclerosis, using extreme unexplained phenotypes of subclinical atherosclerosis will help identifying novel factors which may ultimately lead to innovative therapeutic targets for atherosclerosis and reduce risk of stroke, myocardial infarction and other consequences of atherosclerosis. The specific primary aims of the proposed research are to: (1) identify individuals with unexplained subclinical atherosclerosis (USAth) and unexplained protection against atherosclerosis (UPAth) by generating standardized residual scores in the multivariable regression model from traditional vascular risk factors and carotid artery plaque area burden, a subclinical carotid artery phenotype collected among 1,200 Caribbean Hispanic stroke-free individuals; (2) identify alleles that are associated with USAth and UPAth by performing a genome wide association study; (3) validate these findings in an independent sample of a family-based cohort and in the SHARe Project, and (4) perform follow-up studies of the top 2 most significant SNPs/CNVs identified in both samples to identify the underlying causative variation. The strengths of this proposal include the wealth of baseline data (including carotid ultrasound imaging) that has already been collected as a part of the population-based Northern Manhattan study, the evaluation of innovative risk factors, DNA repository available, carotid imaging performed according to the standardized scanning protocols, a capability of sophisticated ultrasound imaging analyses, genotyping and genetic analyses, and dual PI responsibility to assure a completion of the high quality phenotyping (Dr. T. Rundek, neurology) and genotyping (Dr. S. Blanton, genomics). New quantitative traits developed in this study, "unexplained subclinical atherosclerosis" and "unexplained protection against subclinical atherosclerosis", will make possible to identify novel and previously unsuspected genetic associations for those contributing to the excessive atherosclerosis, and those protective from atherosclerosis.

描述（由申请人提供）：先兆条件或亚临床标志物提供了了解动脉粥样硬化早期决定因素的机会。传统的血管危险因素预测颈动脉斑块的变异不到一半，尽管根据现行指南对传统血管危险因素进行了治疗，但仍有一半的个体会经历斑块进展。与斑块稳定或消退的个体相比，亚临床动脉粥样硬化进展的个体在 5 年内发生中风、心肌梗塞或死亡的风险是其两倍。动脉粥样硬化是一种复杂的疾病，具有很大的遗传因素。参与亚临床颈动脉粥样硬化调节的特定基因多态性及其极端无法解释的表型尚不清楚。利用亚临床动脉粥样硬化的极端无法解释的表型来寻找加速或预防动脉粥样硬化的新等位基因，将有助于识别新的因素，最终可能导致动脉粥样硬化的创新治疗靶点，并降低中风、心肌梗塞和动脉粥样硬化其他后果的风险。拟议研究的具体主要目标是：（1）通过在传统血管危险因素和颈动脉斑块的多变量回归模型中生成标准化残差分数，识别患有不明原因亚临床动脉粥样硬化（USAth）和不明原因动脉粥样硬化保护（UPAth）的个体区域负担，一种亚临床颈动脉表型，收集自 1,200 名加勒比裔西班牙裔无中风患者； (2) 通过进行全基因组关联研究来鉴定与 USAth 和 UPAth 相关的等位基因； (3) 在基于家庭的队列的独立样本和 SHARe 项目中验证这些发现，以及 (4) 对两个样本中确定的前 2 个最显着的 SNP/CNV 进行后续研究，以确定潜在的致病变异。该提案的优势包括作为基于人口的北曼哈顿研究的一部分已经收集的丰富的基线数据（包括颈动脉超声成像）、创新风险因素的评估、可用的 DNA 存储库、根据标准化扫描协议、复杂的超声成像分析、基因分型和遗传分析的能力以及双重 PI 责任，以确保完成高质量的表型分析（T. Rundek 博士，神经病学）和基因分型（S. Blanton 博士，基因组学）。这项研究中开发的新数量特征，“不明原因的亚临床动脉粥样硬化”和“不明原因的亚临床动脉粥样硬化保护”，将有可能确定那些导致过度动脉粥样硬化和防止动脉粥样硬化的新的和以前未被怀疑的遗传关联。