GeneSTAR Research Center - Genetic Studies of Atherosclerosis Risk
Gene Transcripts and Proteomics in Families with Platelet Hyperaggregation

Platelet hyperaggregation is an important intermediate phenotype for myocardial infarction, acute coronary syndromes, and strokes. We have already discovered and replicated GWAS signals for platelet aggregation in two-generational families of premature coronary disease probands (GeneSTAR), European Americans and African Americans. Although platelet aggregation is highly heritable, all of the identified GWAS signals together explain only a small fraction of its variance among individuals. 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. We are also using whole genome sequencing and RNA-seq to address our research questions. 
Our aims are to: (1) use a unique family-based design to examine genes that are differentially expressed in white and African American subjects with platelet hyperaggregation compared to control subjects (as defined from prior studies), (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 expression in hyperaggregating platelets are accurately reflected in corresponding changes in expressed proteins.
This study will produce a complete quantitative inventory of all gene 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. 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.
The study uses sibling pairs and global controls and is operational from 2014-2018. 

Lewis C. Becker, MD
Robert L. Levy Professor, Cardiology
Principal Investigator