title: Role of the CDKN1A/p21, CDKN1C/p57, and CDKN2A/p16 genes in the risk of atherosclerosis and myocardial infarction.
abstract: Atherosclerosis is characterized by excessive proliferation of neointimal leukocytes and vascular smooth muscle cells (VSMCs). In mice, the manipulation of cell cycle inhibitors such as CDKN1B (p27) and CDKN1A (p21) modifies the risk of developing atherosclerosis. In humans, CDKN1A, CDKN1B and CDKN1C (p57) are differentially expressed in normal versus atherosclerotic vessels. A DNA-polymorphism within the CDKN1B promoter has been associated with myocardial infarction (MI). In the present study, we analyzed the effect of CDKN1A, CDKN1C and CDKN2A (p16) polymorphisms on MI-risk. A total of 316 patients (all male, < 55 years) and 434 controls were genotyped, and the allele and genotype frequencies were compared between the two groups. Two CDKN1C polymorphisms, a promoter GT-repeat and a variable number of repeats of the amino acid PAPA-motif, were associated with MI. The presence of two alleles < or = 11-repeats (9/11, 10/11 and 11/11 genotypes) was significantly less frequent among patients (p < 0.001). This difference was also significant when analyzing the subpopulation of smokers (p = 0.004), suggesting a protective role for these low-repeat genotypes (OR = 0.49, 95%CI = 0.32-0.73). The PAPA-BB homozygotes were significantly less frequent in patients, but this could be attributed to a linkage disequilibrium between the 11-repeats and B alleles. No significantly different frequencies between patients and controls for the four CDKN1A (-1026A/G, -754G/C, -369G/C and Ser31Arg) and the three CDKN2A (-523 G/A, +22 G/A and Ala148Thr) polymorphisms was found. In conclusion, we provide here genetic evidence for the association between DNA-variants in the CDKN1C/p57 gene and the risk of atherosclerosis and MI.
authors.affiliation: Genética Molecular and Cardiología, Hospital Central de Asturias, Oviedo, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Rodríguez
authors.forename: Eliecer
authors.initials: E
authors.lastname: Coto
authors.forename: Julián R
authors.initials: JR
authors.lastname: Reguero
authors.forename: Pelayo
authors.initials: P
authors.lastname: González
authors.forename: Vicente
authors.initials: V
authors.lastname: Andrés
authors.forename: Iñigo
authors.initials: I
authors.lastname: Lozano
authors.forename: María
authors.initials: M
authors.lastname: Martín
authors.forename: Victoria
authors.initials: V
authors.lastname: Alvarez
authors.forename: César
authors.initials: C
authors.lastname: Morís
mesh_terms: D000328:Adult; D050197:Atherosclerosis / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics*; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics; D012307:Risk Factors
chemical_list: C493956:CDKN1A protein, human; C493964:CDKN1C protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050761:Cyclin-Dependent Kinase Inhibitor p57