Genetic Determinants of Subclinical Carotid Disease

描述（由申请人提供）：颈动脉内膜中层厚度（IMT）和扩张性分别代表结构性和功能性亚临床颈动脉疾病。它们可以通过超声测量，并且可以用作临床中风/心血管事件的中间表型。研究表明，颈动脉IMT增加或扩张性降低是心肌梗死和卒中的独立危险因素。此外，家族研究报告，在两个中间表型，这表明颈动脉厚度和硬度的发展强烈的遗传影响，明显的遗传力。这些发现保证了将遗传标记映射到这两种表型的奋进。 本研究的主要目的是研究来自北方曼哈顿研究（NOMAS）队列的三个种族/民族（白人、黑人和西班牙裔）中与颈动脉IMT和扩张性相关的遗传多态性。当前应用的优势包括：1）两种表型数据都在大型队列中进行了测量（n约1500）; 2）该队列包括三个种族/民族组，其提供了宝贵的数据源来比较美国三个主要种族/民族组的遗传效应; 3）将分子遗传学、比较基因组学和统计遗传学的新技术应用于我们的研究中; 4）NOMAS家族研究得到了NIH的支持，这将使我们能够通过连锁分析来评估遗传对IMT和扩张性的影响。因此，可以通过不同的研究设计和分析方法验证当前应用的结果。IMT和扩张性的形成可能涉及脂质代谢、分子粘附、内皮功能、平滑肌增殖、炎症反应和血管壁结构完整性。我们建议调查几个潜在的基因参与这些过程。 主要目标：1。目的探讨北方曼哈顿地区3个种族中16个候选基因多态性与颈动脉IMT、扩张性的关系。 2.创建标记单倍型并使用内部新开发的程序进行单倍型分析。 3.探索一种新的统计学方法来评估所有候选基因的总体遗传效应，以获得“全途径”效应。

DESCRIPTION (provided by applicant): Carotid artery intima-media thickness (IMT) and distensibility represent structural and functional subclinical carotid disease, respectively. They can be measured by ultrasound, and can be used as intermediate phenotypes for clinical stroke/cardiovascular events. Studies have shown that increased carotid IMT or decreased distensibility are independent risk factors for myocardial infarction and stroke. Furthermore, family studies reported that appreciable heritability in both intermediate phenotypes, which indicates strong genetic influence on the development of carotid thickness and stiffness. These findings warrant the endeavor to map genetic markers to these two phenotypes. The main goal of this research is to study the genetic polymorphisms associated with carotid IMT and distensibility in the three race/ethnic groups (whites, blacks and Hispanics) from the Northern Manhattan Study (NOMAS) cohort. The strengths of the current application include: 1) both phenotypic data have been measured in a large cohort (n about 1500); 2) the cohort includes three race/ethnic groups, which provides an invaluable data source to compare genetic effect across three major race/ethnic groups in the USA; 3) new technologies in molecular genetics, comparative genomics and statistical genetics will be employed in our studies, and 4) the NOMAS Family Study has been supported by the NIH, which will allow us to evaluate the genetic effect on IMT and distensibility by linkage analysis. Therefore, the results from the current application can be validated from a different study design and analytic approach. The development of IMT and distensibility may involve lipid metabolism, molecule adhesion, endothelial function, smooth muscle proliferation, inflammation and structural integrity of the vessel wall. We propose to investigate several potential genes involved in these processes. Primary Aims: 1. To determine the association between carotid IMT, distensibility and polymorphisms of 16 candidate genes in the three race/ethnic groups from Northern Manhattan. 2. To create marker haplotypes and perform haplotype analysis using in-house newly developed programs. 3. To explore a newly developed statistical method to evaluate the overall genetic effects from all candidate genes to obtain "whole-pathway" effects.