Identifying genes regulating platelet reactivity

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Platelet thrombi in coronary, cerebral and peripheral arteries are the most common cause of global morbidity and mortality. There is a well-established genetic component to the deleterious clinical outcomes of these disorders, but only a small number of platelet gene variations have been associated with these disorders. The goals of this application are to identify the genes and genetic variations responsible for platelet reactivity. Our preliminary data demonstrates that platelet reactivity is both heritable and reproducible. We find that the human platelet aggregation response to submaximal epinephrine stimulation is represented by a bimodal distribution with dramatically different and non-overlapping responses. We have selected groups of unrelated European American and African American subjects whose platelets demonstrate the extremes of platelet responsiveness. Genome wide association studies are powerful approaches for identifying rate- limiting proteins (genes) for this complex physiologic system. In Aim 1 we will genotype >550,000 tagSNPs throughout the genome of our subjects with hyper- and hyporeactive platelets using the Illumina HumanHap550 BeadChip. After performing quality control, analyses will be carried out on genotype and haplotype data. The False Discovery Rate will be used to select a group of SNPs with a false positive rate less than 0.5. To enhance our list of candidates to include novel genes and genes not well-represented in the genome scan platform, in Aim 2 we will perform microarray expression analyses with mRNA from platelets from a subset of European-Americans and African-Americans with extremes of platelet reactivity. In Aim 3 the loci identified in Aim 1 and the genes from Aim 2 will be mapped to obtain SNPs in stronger LD with the causative genetic variant. In Aim 4 we will use the targeted number of SNPs identified in Aim 3 (~300-350) to perform a replication study on all subjects in the Johns Hopkins University GeneSTAR cohort. The successful completion of these studies will result in new insights into platelet physiology and crucial signaling pathways via the discovery of novel genes responsible for platelet function. The variants identified in these genes are expected to be factors modifying thrombosis, hemorrhage and potentially the effects of anti-platelet agents. Our novel approach of using the extremes of a quantitative trait may prove economically valuable for other studies.

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