This project represents a collaborative effort among investigators of the Cardiovascular Health Research Unit, Department of Genome Sciences at the University of Washington (UW), and the multi-center Cardiovascular Health Study (CHS), including the CHS Blood Laboratory at the University of Vermont. The proposal links advances in thrombosis and inflammation biology, large-scale human genomics, and population and statistical genetics, with the unique resources of CHS, a large, bi-racial cohort of older adults. In older men and women without clinically apparent vascular disease, carotid intimal-medial thickness or IMT (a measure of subclinical atherosclerosis), C-reactive protein (a sensitive marker of inflammation), and D-dimer (a global marker of activation of the hemostatic system) predict subsequent clinical events such as MI and stroke. While the therapeutic benefits of thrombolytic therapy and aspirin suggest a major role for clotting and inflammation in the etiology of coronary disease and stroke, the genetic determinants of these risk factors, which are also influenced by traditional lifestyle risk factors such as smoking and obesity, remains largely unexplored in older adults. The setting for this study is the Cardiovascular Health Study, a cohort study of 5888 older adults designed to assess risk factors for stroke and coronary disease. Data on traditional risk factors, on measures of subclinical disease, and cardiovascular events are available to the proposed ancillary study. By integrating recent clinical and experimental data on age-related and vascular bed-specific regulation of blood coagulation, and incorporating complete human genomic DNA sequence variation data from the NHLBI-funded UW Program for Genomic Applications, we propose to evaluate thoroughly the association of thrombosis and inflammation genes with (1) carotid IMT, CRP, and D-dimer levels measured at baseline and (2) incident MI and stroke in adults >65 years old followed for up to 12 years. The strengths of the proposal include a focus on several sets of biologically related genes, the selection of common SNPs based on the complete linkage disequilibrium or common haplotype structure of each candidate gene, and a flexible analytic approach that allows assessment of single-locus and multi-locus genotypes, haplotypes, as well as gene-environment and gene-gene interaction. We expect this multi-disciplinary approach to enable the detection of genetic variants that influence CVD susceptibility or modify the response to conventional cardiovascular risk factors. Understanding the molecular background of these common but complex athero-thrombotic disorders may help identify older individuals at high cardiovascular risk because of genetic or environmental differences in the inflammatory or thrombotic response to advanced atherosclerosis and provide new directions for prevention and treatment of MI and stroke. ? ?
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