Barts and The London School of Medicine and Dentistry, William Harvey Research Institute, Queen Mary University of London, London, UK.
Hum Mol Genet. 2012 Sep 15;21(18):4021-9. doi: 10.1093/hmg/dds224. Epub 2012 Jun 15.
Variation on chromosome 9p21 is associated with risk of coronary artery disease (CAD). This genomic region contains the CDKN2A and CDKN2B genes which encode the cell cycle regulators p16(INK4a), p14(ARF) and p15(INK4b) and the ANRIL gene which encodes a non-coding RNA. Vascular smooth muscle cell (VSMC) proliferation plays an important role in the pathogenesis of atherosclerosis which causes CAD. We ascertained whether 9p21 genotype had an influence on CDKN2A/CDKN2B/ANRIL expression levels in VSMCs, VSMC proliferation and VSMC content in atherosclerotic plaques. Immunohistochemical examination showed that VSMCs in atherosclerotic lesions expressed p16(INK4a), p14(ARF) and p15(INK4b). Analyses of primary cultures of VSMCs showed that the 9p21 risk genotype was associated with reduced expression of p16(INK4a), p15(INK4b) and ANRIL (P = 1.2 × 10(-5), 1.4 × 10(-2) and 3.1 × 10(-9)) and with increased VSMC proliferation (P = 1.6 × 10(-2)). Immunohistochemical analyses of atherosclerotic plaques revealed an association of the risk genotype with reduced p15(INK4b) levels in VSMCs (P = 3.7 × 10(-2)) and higher VSMC content (P = 5.6 × 10(-4)) in plaques. The results of this study indicate that the 9p21 variation has an impact on CDKN2A and CDKN2B expression in VSMCs and influences VMSC proliferation, which likely represents an important mechanism for the association between this genetic locus and susceptibility to CAD.
9p21 染色体上的变异与冠心病 (CAD) 的风险相关。该基因组区域包含 CDKN2A 和 CDKN2B 基因，它们编码细胞周期调节剂 p16(INK4a)、p14(ARF)和 p15(INK4b)以及 ANRIL 基因，该基因编码一种非编码 RNA。血管平滑肌细胞 (VSMC) 的增殖在导致 CAD 的动脉粥样硬化发病机制中起着重要作用。我们确定 9p21 基因型是否会影响 VSMCs 中的 CDKN2A/CDKN2B/ANRIL 表达水平、VSMC 增殖和动脉粥样硬化斑块中的 VSMC 含量。免疫组织化学检查显示，动脉粥样硬化病变中的 VSMCs 表达 p16(INK4a)、p14(ARF)和 p15(INK4b)。对 VSMC 的原代培养分析表明，9p21 风险基因型与 p16(INK4a)、p15(INK4b)和 ANRIL 的表达降低相关（P = 1.2×10(-5)、1.4×10(-2)和 3.1×10(-9)），并且 VSMC 增殖增加（P = 1.6×10(-2)）。对动脉粥样硬化斑块的免疫组织化学分析显示，风险基因型与 VSMCs 中 p15(INK4b)水平降低（P = 3.7×10(-2)）和斑块中 VSMC 含量增加（P = 5.6×10(-4)）相关。这项研究的结果表明，9p21 变异对 VSMCs 中的 CDKN2A 和 CDKN2B 表达有影响，并影响 VSMC 增殖，这可能是该遗传位点与 CAD 易感性相关的重要机制。
