A single-nucleotide polymorphism in the human p27kip1 gene (-838C>A) affects basal promoter activity and the risk of myocardial infarction.
BACKGROUND
Excessive proliferation of vascular smooth muscle cells and leukocytes within the artery wall is a major event in the development of atherosclerosis. The growth suppressor p27kip1 associates with several cyclin-dependent kinase/cyclin complexes, thereby abrogating their capacity to induce progression through the cell cycle. Recent studies have implicated p27kip1 in the control of neointimal hyperplasia. For instance, p27kip1 ablation in apolipoprotein-E-null mice enhanced arterial cell proliferation and accelerated atherogenesis induced by dietary cholesterol. Therefore, p27kip1 is a candidate gene to modify the risk of developing atherosclerosis and associated ischaemic events (i.e., myocardial infarction and stroke).


RESULTS
In this study we found three common single-nucleotide polymorphisms in the human p27kip1 gene (+326T>G [V109G], -79C>T, and -838C>A). The frequency of -838A carriers was significantly increased in myocardial infarction patients compared to healthy controls (odds ratio [OR] = 1.73, 95% confidence interval [95%CI] = 1.12-2.70). In addition, luciferase reporter constructs driven by the human p27kip1 gene promoter containing A at position -838 had decreased basal transcriptional activity when transiently transfected in Jurkat cells, compared with constructs bearing C in -838 (P = 0.04).


CONCLUSIONS
These data suggest that -838A is associated with reduced p27kip1 promoter activity and increased risk of myocardial infarction.
González
Pelayo
P
Laboratorio de Genética Molecular, Instituto de Investigación Nefrológica (IRSIN-FRIAT), and Servicio de Cardiología, Hospital Universitario Central de Asturias (Maternidad), 33006 Oviedo, Spain. layopelayo@mixmail.com <layopelayo@mixmail.com>
Díez-Juan
Antonio
A
Coto
Eliecer
E
Alvarez
Victoria
V
Reguero
Julian R
JR
Batalla
Alberto
A
Andrés
Vicente
V
D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics*; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D019169:Jurkat Cells; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000235:genetics*; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012307:Risk Factors; D014158:Transcription, Genetic
D050760:Cyclin-Dependent Kinase Inhibitor p27