NOVEL FACTORS FOR UNEXPLAINED PHENOTYPES OF SUBCLINICAL CAROTID ATHEROSCLEROSIS

描述（由申请人提供）： 先兆疾病或亚临床标志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方差不到一半，尽管根据目前的指南治疗了传统的血管危险因素，但仍有一半的人经历了斑块进展。亚临床动脉粥样硬化进展的个体与稳定斑块或消退的个体相比，5年内中风、心肌梗死或死亡的风险增加一倍。动脉粥样硬化是一种复杂的疾病，有很大的遗传贡献。参与亚临床颈动脉粥样硬化调节的特定遗传多态性及其极端不明表型尚不清楚。使用亚临床动脉粥样硬化的极端不明表型来寻找加速或防止动脉粥样硬化的新等位基因，将有助于鉴定可能最终导致动脉粥样硬化的创新治疗靶点并降低中风、心肌梗死和动脉粥样硬化的其他后果的风险的新因子。拟议研究的具体主要目的是：（1）通过从传统血管危险因素和颈动脉斑块面积负荷（从1，200名加勒比西班牙裔无卒中个体中收集的亚临床颈动脉表型）的多变量回归模型中生成标准化残差评分，识别患有不明原因的亚临床动脉粥样硬化（USAth）和不明原因的抗动脉粥样硬化保护（UPAth）的个体;（2）通过进行全基因组关联研究来鉴定与USAth和UPAth相关的等位基因;（3）在基于家族的群组的独立样本和SHARe项目中验证这些发现，以及（4）对两个样本中鉴定的前2个最显著的SNP/CNV进行后续研究，以鉴定潜在的致病变异。这一建议的优势包括基线数据丰富（包括颈动脉超声成像），其已经作为基于人群的北方曼哈顿研究的一部分收集，创新风险因素的评估，可用的DNA库，根据标准化扫描方案进行的颈动脉成像，复杂的超声成像分析，基因分型和遗传分析的能力，和双重PI责任，以确保完成高质量的表型分析（T. Rundek，神经病学）和基因分型（S。Blanton，genomics）.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“不明原因的保护对亚临床动脉粥样硬化”，将有可能确定新的和以前未知的遗传协会的过度动脉粥样硬化，和那些保护动脉粥样硬化。

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.