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 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.
van Tiel
Claudia M
CM
Department of Medical Biochemistry, University of Amsterdam, the Netherlands.
Bonta
Peter I
PI
Rittersma
Saskia Z H
SZ
Beijk
Marcel A M
MA
Bradley
Edward J
EJ
Klous
Anita M
AM
Koch
Karel T
KT
Baas
Frank
F
Jukema
J Wouter
JW
Pons
Douwe
D
Sampietro
M Lourdes
ML
Pannekoek
Hans
H
de Winter
Robbert J
RJ
de Vries
Carlie J M
CJ
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
C436291:CDKN1B protein, human; D047908:Intracellular Signaling Peptides and Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27