Atherosclerosis is the major cause of morbidity and mortality in the western world. Studies of atherosclerosis in human subjects are complicated by non- Mendelian inheritance, genetic heterogeneity, a late age of onset, incomplete penetrance, and environmental influences. However, recent advances, including our improved ability to delineate the abnormal physiology related to insulin resistance and associated metabolic syndrome, the ability to assess preclinical physiological and structural aspects of the atherosclerotic process, the discovery of highly polymorphic molecular genetic markers, the development of new strategies for analysis of complex traits, and the relevant statistic programs have put the identification of genes making even modest contributions to the disease within reach. As a consequence, the rate limiting step in gene identification is the study of families in sufficient physiologic detail and in adequate sample size to match the power of the genetic marker and analytic technology. The goal of Project 2 is to utilize our experience in detailed extensive family phenotyping to identify specific genes and regions within the human genome contributing to intermediate phenotypes for atherosclerosis with particular emphasis on structural changes in the vessel wall, defined by a ultrasound assessment of carotid intimal medial thickness (IMT), and insulin resistance and components of the associated metabolic syndrome. A systematic mapping approach is particular appropriate since there are so many potential candidate genes for the various components of the atherosclerosis process. We therefore propose a two stage design consisting of an initial whole genome scan with a 10cM map, followed by fine mapping in selected regions, then confirming the linkage in an independent sample, using highly polymorphic molecular markers in 2 sets of approximately 112 each of extensively phenotyped Mexican-American families with a total of over 1800 sibpairs. The regions for fine mapping will be selected on the basis of the significance level of the linkage analyses, existence of known candidate genes or mouse syntenic regions. The confirmed linkages will be further examined by candidate gene association and stratified analyses.
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