Recent Studies of the Human Chromosome 9p21 Locus, Which Is Associated With Atherosclerosis in Human Populations
Recent Studies of the Human Chromosome 9p21 Locus, Which Is Associated With Atherosclerosis in Human Populations
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DOI：
10.1161/atvbaha.111.232678
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发表时间：
2012-02-01
影响因子：
8.7
通讯作者：
Teupser, Daniel
中科院分区：
文献类型：
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作者：
Holdt, Lesca M.;Teupser, Daniel
染色体9 p21（Chr 9 p21）基因座是在2007年由冠状动脉疾病的独立全基因组关联研究发现的。从那时起，该基因座已经被复制了无数次，可以被认为是当今冠状动脉疾病最强大的遗传标记。随后的研究表明，Chr 9 p21与许多其他心血管疾病特征相关，如颈动脉斑块、中风、动脉瘤、外周动脉疾病、心力衰竭和心血管死亡率，这表明Chr 9 p21在血管病理学中具有更普遍的作用。重要的是，Chr 9 p21与常见的心血管风险因素（如血脂和高血压）缺乏关联，表明该位点通过一种全新的机制发挥作用。挑战之一是Chr 9 p21的核心单倍型块位于基因组中缺乏蛋白质编码基因的区域。最近的研究进展集中在INK 4基因座（ANRIL），这是从Chr 9 p21基因座转录的反义非编码RNA的差异表达，以及在INK 4/ARF基因座附近的蛋白质编码基因的功能研究。新出现的概念表明，ANRIL可能构成表观遗传修饰的调节剂，从而调节心血管风险。在这里，我们回顾了目前的临床，机制和诊断的影响，Chr 9 p21基因座在心血管疾病。（Arterioscler Thromb Vasc Biol.2012;32：196-206.）
The chromosome 9p21 (Chr9p21) locus was discovered in 2007 by independent genome-wide association studies for coronary artery disease. Since then, the locus has been replicated numerous times and can be considered the most robust genetic marker of coronary artery disease today. Subsequent work has shown associations of Chr9p21 with a number of additional cardiovascular disease traits, such as carotid artery plaque, stroke, aneurysms, peripheral artery disease, heart failure, and cardiovascular mortality, suggesting a more general role in vascular pathology. Importantly, Chr9p21 lacks associations with common cardiovascular risk factors, such as lipids and hypertension, indicating that the locus exerts its effect through a completely novel mechanism. One of the challenges is that the core haplotype block at Chr9p21 resides in a region of the genome devoid of protein-coding genes. Recent progress has been made by functional studies focusing on differential expression of antisense noncoding RNA in the INK4 locus (ANRIL), which is transcribed from the Chr9p21 locus, as well as neighboring protein-coding genes at the INK4/ARF locus. The emerging concept suggests that ANRIL might constitute a regulator of epigenetic modification and thus modulate cardiovascular risk. Here, we review the current clinical, mechanistic, and diagnostic implications of the Chr9p21 locus in cardiovascular disease. (Arterioscler Thromb Vasc Biol. 2012;32:196-206.)