Genetic regulation of racial differences in platelet reactivity


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Collapse abstract
Coronary heart disease (CHD) is the most common killer in both whites and blacks. However, blacks have a 2- fold increase in the incidence of CHD as well as a lower long-term survival compared to whites. These differences cannot be fully explained by demographic, clinical, or economic confounders between these groups. As myocardial infarction and stroke typically result from an occlusive platelet thrombus formed at the site of a ruptured atherosclerotic plaque, understanding differences in the mechanisms by which platelets are activated in blacks and whites is expected to aid in our ability to optimally treat these populations following myocardial infarction (MI) and stroke. Our preliminary data demonstrates, for the first time, 1) racial differences in PAR4-mediated platelet aggregation, and 2) platelet mRNAs and microRNAs that are differentially expressed (DE) between blacks and whites and regulate PRA4 activation. The goals of this application are to characterize 1) the critical pathways and proteins responsible for these racial differences in platelet function, and 2 the molecular genetic basis for differences in gene expression. These goals will be addressed with physiology, biochemistry, genomic and cell biology approaches in human platelets and megakaryocytes. Aim 1 will dissect racial differences in platelet function using physiological and biochemical endpoints to assess PAR4 activation kinetics and absolute level of activity. By integrating the information attained in Aim 1, Aim 2 will evaluate novel candidate platelet genes DE expressed between blacks and whites. These genes will be characterized for their potential role in regulating the racial difference in PAR4-mediated reactivity of platelets. In particular, w find phosphatidylcholine transfer protein (PC-TP), is significantly higher in platelets from blacks compared to platelets from whites. PC-TP regulates lipid movement in the cell, a critical process in platelet activation. Several other strong candidate platelet genes - also DE by race - will also be characterized. Aim 3 will focus on novel mechanisms of gene expression that account for racial differences in platelet aggregation. We have identified the first example of miRNAs that are DE by race and by PAR4-mediated platelet aggregation. We will genetically manipulate candidate miRNAs in cultured human megakaryocytes to assess their effects on regulating PAR4-mediated platelet/megakaryocyte reactivity. We will also assess the molecular basis for the differential expression of miRNAs. This study will be the first to characterize racial differences in platelet activation at the signaling, protein and genetic levels. Understanding the racial difference in platelet activity will fill a significant gap in our understanding of why blacs suffer a higher morbidity and mortality than whites following MI and stroke.
Collapse sponsor award id
R01MD007880

Collapse Time 
Collapse start date
2013-07-09
Collapse end date
2019-02-28