Platelets play a major role in the development of atherothrombotic cardiovascular diseases. Platelet hyperaggregation is an important intermediate phenotype for myocardial infarction, acute coronary syndromes, and strokes. We have discovered and replicated GWAS signals for platelet aggregation in two-generational families of premature coronary disease probands (GeneSTAR), 334 European Americans and 232 African Americans. These families are highly enriched with both platelet hyper-aggregation and incident acute cardiovascular events. Although platelet aggregation is highly heritable, all of the identified GWAS signals together explain only a small fraction of its variance among individuals. In addition, most of the identified GWAS signals are located in introns and intergenic regions, so it is not clear how the variant is functionally related to the aggregation response. In this application we propose to discover new pathways regulating platelet aggregation by determining which genes are expressed in subjects with platelet hyperaggregation. By sequencing the entire platelet transcriptome we will identify changes in the amount or quality (e.g., splice variants) of mRNA transcripts that are associated with specific platelet hyperaggregation phenotypes.
Our aims are to: (1) use a unique family-based design to discover the genes that are differentially expressed in white and African American subjects with platelet hyperaggregation compared to control subjects, (2) leverage our prior GWAS to identify eQTLs associated with transcript expression to help prioritize transcripts/genes for further study, and (3) use quantitative mass spectrometry to determine whether changes in gene expression in hyperaggregating platelets are accurately reflected in corresponding changes in expressed proteins. This study will produce a complete quantitative inventory of all mRNA transcripts present in platelets, as well as a complete eQTL map of genetic loci responsible for transcript expression specifically in platelets in both European and African Americans. The inclusion of both ethnicities will allow us to both replicate mRNA findings and amplify biological insights, given the different LD patterns of the two groups. The results will provide new insights into the functional pathways mediating the most important genomic associations with platelet hyperaggregation identified in previous GWAS studies. We expect that our studies will identify previously unknown proteins and biological pathways responsible for platelet hyperaggregation, which may then serve as new therapeutic targets and ultimately more effective and specific approaches for inhibition of platelet function in the large number of people at risk for thrombotic vascular occlusions being treated with anti-platelet therapy.
Platelets in the circulating blood can stick together (aggregate), clot and cause heart attack or stroke. We will develop a better understanding of the process through sequencing genes that are transcribed in platelets and comparing the patterns of gene expression in people whose platelets have very high levels of aggregation to those with normal aggregation. The results will lead to better and more specific treatments to reduce platelet aggregation in people who are at risk for complications of arterial occlusions.