Aggregation of activated platelets on atherosclerotic plaques initiates thromboses of the arterial system, resulting in ischemic syndromes. The propensity of platelets to aggregate in vivo is characterized by a variety of in vitro assays. We and others have demonstrated that many of these platelet function assays are moderately to highly heritable in populations at increased risk for atherosclerosis, supporting the hypothesis that genetic variations underlie individual variability in the tendency for arterial thrombosis. Inhibition of platelets by low dose aspirin (ASA) is also a heritable trait and genetic variations may be in part responsible for responsiveness to ASA. We have extensively characterized native platelet function and platelet function after low dose ASA (81 mg/day for 14 days) in 2000 individuals from 500 2-generational families with premature coronary artery disease (60% white, 40% African American) participating in the Genetic Study of Aspirin Responsiveness (GeneSTAR) and the Johns Hopkins Sibling and Family Heart Study. All study participants have had a 500 short tandem repeat (STR) genome scan. The overall goal of this proposal is to identify genes that modify the function of platelets, both under """"""""normal native"""""""" conditions, and following low dose ASA. We propose to perform high density single nucleotide polymorphism (SNP) genotyping (550,000 SNPs, using the Illumina HumanHap550 BeadChip) covering the entire genome at an average 6kb density, on the DNA samples from the GeneSTAR participants phenotyped for platelet function. We propose to determine whether any genomic loci are associated with quantitative platelet phenotypes prioritized for high heritability, biological interest, and/or linkage to STR markers, using family based association analysis, with joint modeling of linkage and association. Phenotypes of highest priority include aggregation induced by collagen, adenosine diphosphate (ADP), arachidonic acid (AA), and epinephrine in platelet rich plasma (PRP), ATP release induced by AA, and urinary levels of the prostaglandin metabolite, 11 dehydrothromboxane B2. We will examine our findings in relation to three baseline native platelet phenotypes (collagen-, epinephrine-, and ADP-induced aggregation in PRP) in the Framingham Heart Study database. This study represents the first genome -wide SNP association study of comprehensive platelet function and should lead to novel tailored anti-platelet therapy for the prevention of vascular thromboses.
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