Almontashiri Naif A M
Department of Pathology, Massachusetts General Hospital, Harvard University, Boston, USA.
J Taibah Univ Med Sci. 2017 Apr 25;12(3):199-204. doi: 10.1016/j.jtumed.2017.03.001. eCollection 2017 Jun.
The 9p21.3 risk locus is the first locus to be associated with an increased risk of coronary artery disease (CAD)-related events and many other phenotypes. This locus contains 59 single nucleotide polymorphisms (SNPs) in a region with multiple long range enhancers and long non-coding RNAs (lncRNAs) that affect the expression of neighbouring genes, cyclin-dependent kinase 2A and 2B (CDKN2A and CDKN2B), which are required for controlling vascular smooth muscle cell proliferation and ageing. Several studies have attempted to identify the precise mechanism by which this locus exerts its pathogenic effect to increase the risk of CAD-related events. In this review, we will highlight the major advances in our understanding of the genotype-phenotype correlation at the mechanistic and phenotypic levels. The high population attributable risk of the 9p21.3 risk locus, mechanistic knowledge acquired thus far, and ongoing research efforts could facilitate the design of novel therapeutic molecules to reduce the risk of CAD and its related events.
9p21.3风险基因座是首个与冠状动脉疾病（CAD）相关事件及许多其他表型风险增加相关的基因座。该基因座在一个具有多个远距离增强子和长链非编码RNA（lncRNA）的区域内包含59个单核苷酸多态性（SNP），这些增强子和lncRNA会影响邻近基因细胞周期蛋白依赖性激酶2A和2B（CDKN2A和CDKN2B）的表达，而这两个基因是控制血管平滑肌细胞增殖和衰老所必需的。多项研究试图确定该基因座发挥致病作用以增加CAD相关事件风险的确切机制。在本综述中，我们将重点介绍在机制和表型水平上对基因型-表型相关性理解的主要进展。9p21.3风险基因座的高人群归因风险、迄今获得的机制知识以及正在进行的研究工作，可能有助于设计新型治疗分子以降低CAD及其相关事件的风险。
