Ottawa Hospital Research Institute, 451 Smyth Road, RGN Hall, Rm 2422, K1H 8M5, Ottawa, Ontario, Canada.
Curr Cardiol Rep. 2014 Jul;16(7):502. doi: 10.1007/s11886-014-0502-7.
The 9p21.3 locus was the first to yield to genome-wide association studies (GWAS) seeking common genetic variants predisposing to increased risk of coronary artery atherosclerotic disease (CAD). The 59 single nucleotide polymorphisms that show highest association with CAD are clustered in a region 100,000 to 150,000 base pairs 5' to the cyclin-dependent kinase inhibitors CDKN2B (coding for p15(ink4b)) and CDKN2A (coding for p16(ink4a) and p14(ARF)). This region also covers the 3' end of a long noncoding RNA transcribed antisense to CDKN2B (CDKN2BAS, aka ANRIL for antisense noncoding RNA at the ink4 locus) whose expression has been linked to chromatin remodeling at the locus. Despite intensive investigation over the past 7 years, the functional significance of the 9p21.3 locus remains elusive. Other variants at this locus have been associated with glaucoma, glioma, and type 2 diabetes mellitus, diseases that implicate tissue-resident macrophages. Here, we review the evidence that genetic variants at 9p21.3 disrupt tissue-specific enhancers and propose new insights to guide future studies.
9p21.3 基因座是第一个通过全基因组关联研究（GWAS）发现易患冠状动脉粥样硬化性疾病（CAD）风险增加的常见遗传变异的基因座。与 CAD 相关性最高的 59 个单核苷酸多态性聚集在一个 100,000 到 150,000 碱基对的区域 5'，位于细胞周期蛋白依赖性激酶抑制剂 CDKN2B（编码 p15(ink4b)）和 CDKN2A（编码 p16(ink4a)和 p14(ARF)）的上游。该区域还覆盖了 CDKN2B 反义转录的长非编码 RNA（CDKN2BAS，又名 ANRIL 代表 ink4 基因座的反义非编码 RNA）的 3'端，其表达与该基因座的染色质重塑有关。尽管在过去的 7 年中进行了深入研究，但 9p21.3 基因座的功能意义仍然难以捉摸。该基因座的其他变体与青光眼、神经胶质瘤和 2 型糖尿病有关，这些疾病涉及组织驻留巨噬细胞。在这里，我们回顾了 9p21.3 上的遗传变异破坏组织特异性增强子的证据，并提出了新的见解来指导未来的研究。
