Transcription Factor RUNX1 Regulates Platelet (Phosphatidylcholine Transfer Protein): Implications for Cardiovascular Events: Differential Effects of RUNX1 Variants.

BACKGROUND

PCTP (phosphatidylcholine transfer protein) regulates the intermembrane transfer of phosphatidylcholine. Higher platelet PCTP expression is associated with increased platelet responses on activation of protease-activated receptor 4 thrombin receptors noted in black subjects compared with white subjects. Little is known about the regulation of platelet . Haplodeficiency of RUNX1, a major hematopoietic transcription factor, is associated with thrombocytopenia and impaired platelet responses on activation. Platelet expression profiling of a patient with a loss-of-function mutation revealed a 10-fold downregulation of the gene compared with healthy controls.

METHODS

We pursued the hypothesis that is regulated by RUNX1 and that expression is correlated with cardiovascular events. We studied RUNX1 binding to the promoter using DNA-protein binding studies and human erythroleukemia cells and promoter activity using luciferase reporter studies. We assessed the relationship between and in peripheral blood RNA and and death or myocardial infarction in 2 separate patient cohorts (587 total patients) with cardiovascular disease.

RESULTS

Platelet PCTP protein in the patient was reduced by ≈50%. DNA-protein binding studies showed RUNX1 binding to consensus sites in ≈1 kB of promoter. expression was increased with overexpression and reduced with knockdown in human erythroleukemia cells, indicating that is regulated by RUNX1. Studies in 2 cohorts of patients showed that expression in blood correlated with gene expression; expression was higher in black compared with white subjects and was associated with future death/myocardial infarction after adjustment for age, sex, and race (odds ratio, 2.05; 95% confidence interval 1.6-2.7; <0.0001). expression is known to initiate at 2 alternative promoters, a distal P1 and a proximal P2 promoter. In patient cohorts, there were differential effects of isoforms on expression with a negative correlation in blood between expressed from the P1 promoter and expression.

CONCLUSIONS

is a direct transcriptional target of RUNX1. expression is associated with death/myocardial infarction in patients with cardiovascular disease. RUNX1 regulation of may play a role in the pathogenesis of platelet-mediated cardiovascular events.