Colorado PROFILES, The Colorado Clinical and Translational Sciences Institute (CCTSI)
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Thrombosis genetics in African Americans

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ABSTRACT Cardiovascular diseases are the leading cause of death in the United States, and disproportionate rates are seen in minority African American populations. Thrombosis and vascular inflammation are important contributors to atherosclerotic plaque rupture and vascular occlusion that underlie myocardial infarction, ischemic stroke, as well as venous thromboembolic disease. The identification of novel biomarkers and their assessment in different ethnic populations can augment the information obtained from traditional CVD risk factors as well as illuminate underlying disease mechanisms and health disparities. While blood biomarkers have been shown to be critically important in the study of CVD, there is a deficit of studies of these measures in African American populations. Preliminary data suggest that thrombin generation, as quantified ex vivo by plasma measurement of endogenous thrombin potential (ETP) is a novel approach to understanding the connection of both the intrinsic and extrinsic coagulation pathways to thrombus formation in vivo. Whole genome sequence (WGS) data, including both coding and functional noncoding variants, are required to identify the full spectrum of contributions of rare variants to common diseases. WGS data are particularly important among non-European ancestry groups, where there is still relatively limited genomic information. Using stored baseline Jackson Heart Study (JHS) plasma samples from 3,500 African Americans, we propose to measure several emerging thrombosis and inflammation plasma biomarkers (endogenous thrombin potential, fibrinogen gamma', coagulation factors VIII and VIIa, soluble interleukin-2 receptor, soluble CD14, and soluble CD163) that are likely to reflect and/or account for increased thrombogenicity and therefore may contribute to higher rates of CVD in African Americans. We will assess the association of thrombosis biomarkers and biomarker-associated genetic variants with more complex subclinical and clinical CVD endpoints available in JHS and other African American cohorts, including REGARDS. By adding these key measures of thrombosis and inflammation to the JHS and REGARDS data sets, utilizing existing whole genome sequence data available through the NHLBI TOPMed project, and using innovative analytical and population genetic approaches, we will be able to greatly expand our knowledge of the role of thrombosis and inflammation in CVD health disparities.
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