Genetic Determinants of Subclinical Carotid Disease

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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.