Epidemiology of Vascular Inflammation & Atherosclerosis

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DESCRIPTION (provided by applicant): Currently, the predominant hypothesis regarding atherosclerosis is that it is in major part driven by two independent pathways: hyperlipidemia (the "stimulation") and inflammation (the "response"). Although vascular cells mediate the influence of inflammation on atherosclerosis, very little is known about vascular cell epidemiology and the relationship of vascular cell phenotypes to atherosclerosis. Our main hypothesis is that variation in vascular cell biology is related to the population variation in atherosclerosis. To explore this hypothesis, we propose to use samples from a 1000-person subset of the large epidemiological study MESA (Multi-Ethnic Study of Atherosclerosis) in which coronary calcification, carotid wall thickness, and other estimates of atherosclerosis have already been collected. In Specific Aim 1 we propose to ascertain new cellular phenotypes and determine their distributions and cross-sectional associations with atherosclerosis. We will study: the innate immune response (monocyte activation using as a marker Tissue Factor expression, based on stimulation with three agonists; Natural Killer cell counts, and gamma-delta T cell counts); the adaptive immune response (distributions of Th1 and Th2 T Helper cells, and memory T cells), and vessel integrity (circulating endothelial progenitor cells). In Specific Aim 2 we propose to measure plasma constituents related to these cellular phenotypes, including IgG subclass distribution, IgE, antibodies to Heat Shock proteins and Ox-LDL, IL-10, and Endothelial Protein C Receptor; and to determine the relationship of these measures, plus other inflammation measures in the MESA dataset, to both the cellular phenotypes and atherosclerosis. In Specific Aim 3 we propose to develop for epidemiological use, and begin to apply, advanced molecular and cellular phenotypes such as IgG subclass-specific anti-Ox-LDL antibodies, monocyte CRP-mediated LDL uptake, T Cell Receptor-dependent gamma-delta T Cell subsets, and T cell and monocyte cytokine expression profiles. We believe it is critical to elucidate the phenotypic variation in inflammation-related pathways and the contribution of this variation to atherosclerosis, so that we may better understand the pathophysiology, develop better methods for assessing risk, and produce more effective interventions. In addition, these new phenotypes will prove useful as intermediate phenotypes for future studies of the role of genetic variation in human biology and disease.