NOVEL FACTORS FOR UNEXPLAINED PHENOTYPES OF SUBCLINICAL CAROTID ATHEROSCLEROSIS

描述(由申请人提供)： 前驱状态或亚临床标记物为了解动脉粥样硬化的早期决定因素提供了机会。传统的血管危险因素预测颈动脉斑块的变异不到一半，尽管根据目前的指南接受了传统的血管危险因素的治疗，但仍有一半的人经历了斑块恶化。与斑块稳定或消退的患者相比，亚临床动脉粥样硬化进展的患者在5年内发生中风、心肌梗死或死亡的风险是前者的两倍。动脉粥样硬化是一种复杂的疾病，有很大的遗传因素。参与亚临床颈动脉粥样硬化调控的特定基因多态及其极端未知的表型尚不清楚。利用无法解释的亚临床动脉粥样硬化的极端表型，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目标，并降低中风、心肌梗死和其他动脉粥样硬化后果的风险。拟议研究的具体主要目标是：(1)通过从传统血管风险因素和颈动脉斑块面积负荷(从1,200名加勒比拉美裔无中风患者中收集的亚临床颈动脉表型)的多变量回归模型中产生标准化残差分数，识别患有不明原因的亚临床动脉硬化(USAth)和不明原因的动脉粥样硬化保护(UPAth)的个体；(2)通过进行全基因组关联研究，识别与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两个最显著的SNPs/CNV进行跟踪研究，以确定潜在的原因变异。这一建议的优势包括作为曼哈顿北部人群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进行的颈动脉成像、复杂的超声成像分析、基因分型和基因分析以及确保完成高质量表型分析(T.Rundek博士，神经病学)和基因分型(S.Blanton博士，基因组学)的双重PI责任。在这项研究中开发的新的数量性状，“不明原因的亚临床动脉粥样硬化”和“不明原因的对亚临床动脉粥样硬化的保护作用”，将有可能识别那些导致过度动脉粥样硬化的人和那些对动脉粥样硬化具有保护作用的人的新的和以前未被怀疑的基因关联。

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.