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

• 批准号: 8791485
• 负责人: SUSAN HALLORAN BLANTON
• 金额: $ 9.88万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8791485
• 关键词: Alleles; Area; Atherosclerosis; Blood Vessels; Cardiovascular Diseases; Caribbean region; Carotid Arteries; Carotid Artery Plaques; Carotid Atherosclerotic Disease; Cause of Death; Cessation of life; Cholesterol Homeostasis; Clinical; Complex; Copy Number Polymorphism; DNA Repository; Data; Development; Diabetes Mellitus; Diet; Disease Outcome; Dyslipidemias; Environmental Risk Factor; Etiology; Evaluation Studies; Family; Genes; Genetic; Genetic Determinism; Genetic Polymorphism; Genomics; Genotype; Guidelines; Health; Heritability; Hispanics; Human; Hypertension; Image; Image Analysis; Individual; Inflammatory; Ischemic Stroke; Lead; Lipids; Measures; Modeling; Molds; Myocardial Infarction; Neurology; Phenotype; Population; Process; Protocols documentation; Regulation; Research; Residual state; Resources; Risk; Risk Factors; Sample Size; Sampling; Scanning; Side; Signal Transduction; Single Nucleotide Polymorphism; Smoking; Smooth Muscle; Staging; Stroke; System; 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

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）： 前体的条件或亚临床标记为了解动脉粥样硬化的早期决定因素提供了机会。根据当前的指南，传统的血管危险因素预测，尽管传统的血管危险因素治疗了传统的血管危险因素，但颈动脉斑块和一半的个体的差异的一半不到一半。与具有稳定的斑块或回归的人相比，亚临床动脉粥样硬化进展的个体在5年内的风险是中风，心肌梗塞或死亡的两倍。动脉粥样硬化是一种复杂的疾病，具有实质性的遗传贡献。尚不清楚参与亚临床颈动脉粥样硬化及其极端无法解释的表型的特定遗传多态性。寻找加速或免受动脉粥样硬化的新等位基因，使用亚临床动脉粥样硬化的极端无法解释的表型将有助于识别新的因素，这些因素最终可能导致动脉粥样硬化的创新治疗靶标，并减少中风的风险，心肌梗死和动脉粥样硬化的其他后果。 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无中风的个体； （2）通过进行基因组广泛的关联研究来识别与USATH和UPATH相关的等位基因； （3）在基于家庭的队列和共享项目的独立样本中验证这些发现，以及（4）对两个样本中鉴定的前2个最重要的SNP/CNV进行后续研究，以识别潜在的病因变异。 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完成高质量表型（T. Rundek博士，神经病学）和基因分型（S. Blanton博士，基因组学）。在这项研究中开发的新定量性状，“无法解释的亚临床动脉粥样硬化”和“无法解释的针对亚临床动脉粥样硬化的保护”，将有可能识别有助于过度动脉粥样硬化的人，以及那些保护性动脉粥样硬化的人，以及那些保护性动脉粥样硬化的人。