Institute of Laboratory Medicine, Ludwig-Maximilians-University Munich, Munich, Germany.
Arterioscler Thromb Vasc Biol. 2012 Feb;32(2):196-206. doi: 10.1161/ATVBAHA.111.232678.
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.
9p21 染色体（Chr9p21）位点于 2007 年通过独立的全基因组关联研究发现，与冠状动脉疾病有关。从那时起，该位点已经被多次复制，可以被认为是当今冠状动脉疾病最可靠的遗传标志物。随后的研究表明，Chr9p21 与许多其他心血管疾病特征有关，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，这表明它在血管病理学中具有更普遍的作用。重要的是，Chr9p21 与常见的心血管危险因素（如脂质和高血压）没有关联，表明该位点通过全新的机制发挥作用。其中一个挑战是 Chr9p21 核心单倍型块位于基因组中没有蛋白质编码基因的区域。最近的研究进展集中在 INK4 基因座（ANRIL）的反义非编码 RNA 差异表达的功能研究上，该 RNA 由 Chr9p21 基因座转录，以及 INK4/ARF 基因座的相邻蛋白质编码基因。新兴的概念表明，ANRIL 可能是表观遗传修饰的调节剂，从而调节心血管风险。在这里，我们综述了 Chr9p21 位点在心血管疾病中的临床、机制和诊断意义。
