title: p27kip1-838C>A single nucleotide polymorphism is associated with restenosis risk after coronary stenting and modulates p27kip1 promoter activity.
abstract: 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.
  
  
  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.
authors: Department of Medical Biochemistry, University of Amsterdam, the Netherlands.
authors: Claudia M
authors: CM
authors: van Tiel
authors: Peter I
authors: PI
authors: Bonta
authors: Saskia Z H
authors: SZ
authors: Rittersma
authors: Marcel A M
authors: MA
authors: Beijk
authors: Edward J
authors: EJ
authors: Bradley
authors: Anita M
authors: AM
authors: Klous
authors: Karel T
authors: KT
authors: Koch
authors: Frank
authors: F
authors: Baas
authors: J Wouter
authors: JW
authors: Jukema
authors: Douwe
authors: D
authors: Pons
authors: M Lourdes
authors: ML
authors: Sampietro
authors: Hans
authors: H
authors: Pannekoek
authors: Robbert J
authors: RJ
authors: de Winter
authors: Carlie J M
authors: CJ
authors: de Vries
mesh_terms: D000368:Aged; D015906:Angioplasty, Balloon, Coronary; D002455:Cell Division / Q000502:physiology; D003324:Coronary Artery Disease / Q000453:epidemiology / Q000235:genetics / Q000628:therapy*; D023903:Coronary Restenosis / Q000453:epidemiology* / Q000235:genetics*; D050760:Cyclin-Dependent Kinase Inhibitor p27; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics; D012307:Risk Factors; D015607:Stents
chemical_list: C436291:CDKN1B protein, human; D047908:Intracellular Signaling Peptides and Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27