Circadian clock genes cause activation of the human PAI‐1 gene promoter with 4G/5G allelic preference

Increased plasminogen activator inhibitor‐1 (PAI‐1) activity is associated with greater risk of myocardial infarction. PAI‐1 expression is regulated by a 4G/5G promoter polymorphism. The 4G allele is associated with higher PAI‐levels and greater circadian variation. Here we show that clock protein heterodimers BMAL/CLOCK cause greater activation (≈2‐fold, P < 0.05) of the 4G allele. Site‐directed mutagenesis studies suggest that clock genes act on two canonical E‐boxes to regulate PAI‐1 promoter activity. These results identify a potential novel mechanism whereby allele‐specific clock genes – mediated modulation of PAI‐1 expression may contribute to circadian variation in cardiac risk.

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