Pharmacogenocis of PAR4: PAR4 Polymorphism Determines Platelet Response in the Presence of Dual Anti-Platelet Therapy

Abstract

Aberrant platelet activation contributes to the mortality associated with coronary heart disease (CHD). Our lab group has recently shown that platelets from black donors were hyper-responsive to activation of the thrombin receptor Protease-Activated Receptor-4 (PAR4) compared to platelets from white donors. The racial difference observed through PAR4 persists in platelets treated ex vivo with dual antiplatelet inhibitors (COX-1 and P2Y12 receptor inhibitors), a standard of care for many CHD patients. The racial difference in PAR4 signaling is largely attributable to one PAR4 variant more frequently expressed in blacks than whites, PAR4 T120A. Independent of race, T120 is associated with greater PAR4-mediated platelet reactivity compared to the A120 variant. The role PAR4 variation plays in regulating thrombin-mediated platelet activation in CHD has not been elucidated to date. We hypothesize that people homozygous for the T120 will have an increase in PAR4-mediated platelet reactivity compared to patients homozygous for A120. To investigate this hypothesis, we studied PAR4 signaling in platelets obtained from healthy donors. Platelet activity was assessed in each subject at the beginning of the study. Subsequently subjects were placed on a 7-day treatment of either COX-1 or P2Y12 inhibitors and on day 7 their blood was again drawn and tested for PAR4-AP-mediated platelet activation. Subjects who are homozygous for T120, have an increase in platelet reactivity as measured by aggregation, αIIbβ3 activation and granule secretion compared to individuals who are homozygous for A120. Further distal signaling nodes such as calcium and Rap1 are hyperactive in individuals who are homozygous for T120. This study reinforces the personalized medicine approach to therapeutic intervention and challenges the one size fits all approach which often leaves at risk populations without adequate protection from thrombotic events and stroke. This study was supported in part by grants MD007880, GM105671, and HL 114405 (MH) from the NIH. DisclosuresNo relevant conflicts of interest to declare.