Recent data suggest that patients with both acute and chronic cardiovascular disease (CVD) have notonly enhanced platelet function, but also increased interactions between platelets and the inflammatoryprocess. Platelets lead to acute thrombotic occlusion and also contribute to the chronic process ofatherosclerosis. Whereas established risk factors, inflammatory and thrombotic biomarkers, and genotypicvariations have been examined extensively to predict CVD events, methods utilizing gene expressionprofiles have not been reported from large population-based studies. In preliminary hospital-based data, wefound distinct patterns of platelet gene expression in patients with CVD including enhanced expression of theinflammatory Toll receptors and 5-lipoxygenase. Importantly, these proteins all stimulate the pro-inflammatory NFkappa-B signaling pathway that leads to expression of specific pro-inflammatory andthrombotic genes. Expression of the NFkappa-B dependent genes cyclooxygehase 2 and interleukin 6 werealso found to be increased. Previously, we have measured systemic biomarkers of vascular inflammation inthe community-based sample of 3500 middle-aged and elderly men and women of the Framingham HeartStudy (FHS) Offspring Study. In these subjects, inflammatory biomarkers were related to traditional CVDrisk factors, and prevalent clinical and subclinical CVD. However, a large proportion of the variability invascular disease and thrombosis remains unexplained and the contribution of gene expression fromcirculating peripheral cells is unknown. The central hypothesis of this proposal is that increased thromboticand inflammatory pathways specifically mediated by NFkappa-B are a pro-atherothrombotic phenotype andcan be measured as enhanced gene and biomarker expression due to NFkappa-B dependent activity. Wehypothesize that the expression of these genes is itself a proatherosclerotic phenotype that is influenced byboth environmental factors and genetic variability. We propose the following questions:1. Is stimulation of the NFkappa-B pathway associated with increased expression of relevant markers ofenhanced thrombosis and inflammation?2. What is the relation between NFkappa-B dependent expression (RNA) and the relevant genotypes(DNA)?3. Do established CVD risk factors correlate with NFkappa-B dependent changes in platelet and leukocytegene expression in community-based individuals?4. Do changes in gene expression in platelets and leukocytes predict subclinical and clinical CVD?
