Rodríguez Isabel, Coto Eliecer, Reguero Julián R, González Pelayo, Andrés Vicente, Lozano Iñigo, Martín María, Alvarez Victoria, Morís César
Genética Molecular and Cardiología, Hospital Central de Asturias, Oviedo, Spain.
Cell Cycle. 2007 Mar 1;6(5):620-5. doi: 10.4161/cc.6.5.3927. Epub 2007 Mar 31.
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.
动脉粥样硬化的特征是内膜白细胞和血管平滑肌细胞（VSMC）过度增殖。在小鼠中，对细胞周期抑制剂如CDKN1B（p27）和CDKN1A（p21）的操控会改变动脉粥样硬化的发病风险。在人类中，CDKN1A、CDKN1B和CDKN1C（p57）在正常血管与动脉粥样硬化血管中的表达存在差异。CDKN1B启动子内的一个DNA多态性与心肌梗死（MI）相关。在本研究中，我们分析了CDKN1A、CDKN1C和CDKN2A（p16）多态性对MI风险的影响。对总共316例患者（均为男性，年龄<55岁）和434例对照进行基因分型，并比较两组之间的等位基因和基因型频率。CDKN1C的两个多态性，即启动子GT重复序列和氨基酸PAPA基序的可变重复数，与MI相关。患者中两个等位基因≤11重复（9/11、10/11和11/11基因型）的存在频率显著较低（p<0.001）。在分析吸烟者亚组时，这种差异也很显著（p = 0.004），表明这些低重复基因型具有保护作用（OR = 0.49，95%CI = 0.32 - 0.73）。患者中PAPA - BB纯合子的频率显著较低，但这可能归因于11重复序列与B等位基因之间的连锁不平衡。未发现CDKN1A的四个多态性（-1026A/G、-754G/C、-369G/C和Ser31Arg）以及CDKN2A的三个多态性（-523 G/A、+22 G/A和Ala148Thr）在患者和对照之间的频率有显著差异。总之，我们在此提供了CDKN1C/p57基因中的DNA变异与动脉粥样硬化和MI风险之间关联的遗传学证据。
