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(Circulation. 2009;120:669-676.)
© 2009 American Heart Association, Inc.

Interventional Cardiology

p27^kip1–838C>A Single Nucleotide Polymorphism Is Associated With Restenosis Risk After Coronary Stenting and Modulates p27^kip1 Promoter Activity

Claudia M. van Tiel, PhD^*; Peter I. Bonta, MD^*; Saskia Z.H. Rittersma, MD, PhD; Marcel A.M. Beijk, MD; Edward J. Bradley, BAS; Anita M. Klous, BSc; Karel T. Koch, MD, PhD; Frank Baas, PhD; J. Wouter Jukema, MD, PhD; Douwe Pons, PhD; M. Lourdes Sampietro, PhD; Hans Pannekoek, PhD; Robbert J. de Winter, MD, PhD; Carlie J.M. de Vries, PhD

From the Department of Medical Biochemistry (C.M.v.T., P.I.B., A.M.K., H.P., C.J.M.d.V.), Department of Cardiology (S.Z.H.R., M.A.M.B., K.T.K., R.J.d.W.), and Neurogenetics Laboratory (E.J.B., F.B.), Academic Medical Center, University of Amsterdam, Amsterdam, and Department of Cardiology, Leiden University Medical Center, Leiden (J.W.J., D.P., M.L.S.), the Netherlands.

Correspondence to Carlie J.M. de Vries, PhD, Academic Medical Center K1–113, University of Amsterdam, Meibergdreef 15, 1105 AZ, Amsterdam, the Netherlands. E-mail C.J.deVries{at}amc.uva.nl

Received December 8, 2008; accepted June 19, 2009.

Background— The cyclin-dependent kinase inhibitor p27^kip1 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 p27^kip1 may serve as a useful tool in risk stratification for in-stent restenosis.

Methods and Results— Three single nucleotide polymorphisms concerning the p27^kip1 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 p27^kip1-838C>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 p27^kip1-79C>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 p27^kip1 transcriptional activity of the –838A allele containing promoter.

Conclusions— Patients with the p27^kip1-838AA 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.

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Clinical Summaries
Circulation 2009 120: 647-648. [Extract] [Full Text]