Genetic Determinants of Subclinical Carotid Disease

描述(申请人提供)：颈动脉内中膜厚度(IMT)和扩张性分别代表结构性和功能性亚临床颈动脉疾病。它们可以通过超声波测量，并可用作临床中风/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中风的独立危险因素。此外，家族性研究报告了这两种中间表型的可察觉的遗传力，这表明遗传对颈动脉厚度和僵硬的发展有很强的影响。这些发现证明了将遗传标记定位于这两种表型的努力。 本研究的主要目的是从曼哈顿北部研究(NOMAS)队列研究三个种族/民族(白人、黑人和西班牙裔)中与颈动脉内膜厚度和扩张性相关的基因多态性。当前应用程序的优势包括：1)在大型队列中测量了两个表型数据(n约1500)；2)队列包括三个种族/民族，这为比较美国三个主要种族/民族的遗传效应提供了宝贵的数据源；3)分子遗传学、比较基因组学和统计遗传学的新技术将被用于我们的研究；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的影响和可扩充性。因此，可以从不同的研究设计和分析方法来验证当前应用的结果。IMT和扩张性的发展可能涉及脂代谢、分子黏附、内皮功能、平滑肌增殖、炎症和血管壁的结构完整性。我们建议研究与这些过程有关的几个潜在基因。 主要目的：1.探讨曼哈顿北部三个人种/民族16个候选基因与颈动脉内膜中层厚度、扩张性的关系。2.使用内部新开发的程序创建标记单倍型并进行单倍型分析。3.探索一种新的统计方法来评估所有候选基因的整体遗传效应，以获得“全程”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.