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p27kip1–838C>A Single Nucleotide Polymorphism Is Associated With Restenosis Risk After Coronary Stenting and Modulates p27kip1 Promoter Activity

Background— The cyclin-dependent kinase inhibitor p27kip1 is a key regulator of smooth muscle cell and leukocyte proliferation in vascular disease, including in-stent restenosis. We therefore hypothesized that common genetic variations or single nucleotide polymorphisms in p27kip1 may serve as a useful tool in risk stratification for in-stent restenosis. Methods and Results— Three single nucleotide polymorphisms concerning the p27kip1 gene (−838C>A, rs36228499; −79C>T, rs34330; +326G>T, rs2066827) were determined in a cohort of 715 patients undergoing coronary angioplasty and stent placement. We discovered that the p27kip1-838C>A single nucleotide polymorphism is associated with clinical in-stent restenosis; the −838AA genotype decreases the risk of target vessel revascularization (hazard ratio, 0.28; 95% confidence interval, 0.10 to 0.77). This finding was replicated in another cohort study of 2309 patients (hazard ratio, 0.61; 95% confidence interval, 0.40 to 0.93). No association was detected between this end point and the p27kip1-79C>T and +326G>T single nucleotide polymorphisms. We subsequently studied the functional importance of the −838C>A single nucleotide polymorphism and detected a 20-fold increased basal p27kip1 transcriptional activity of the −838A allele containing promoter. Conclusions— Patients with the p27kip1-838AA genotype have a decreased risk of in-stent restenosis corresponding with enhanced promoter activity of the −838A allele of this cell-cycle inhibitor, which may explain decreased smooth muscle cell proliferation.