Holdt Lesca M, Teupser Daniel
Institute of Laboratory Medicine, University Hospital, LMU Munich, Munich, Germany.
Front Cardiovasc Med. 2018 Nov 6;5:145. doi: 10.3389/fcvm.2018.00145. eCollection 2018.
Ever since the first genome-wide association studies (GWAS) on coronary artery disease (CAD), the Chr9p21 risk locus has emerged as a top signal in GWAS of atherosclerotic cardiovascular disease, including stroke and peripheral artery disease. The CAD risk SNPs on Chr9p21 lie within a stretch of 58 kilobases of non-protein-coding DNA, containing the gene body of the long noncoding RNA (lncRNA) (). How risk is affected by the Chr9p21 locus in molecular detail is a matter of ongoing research. Here we will review recent advances in the understanding that serves as a key risk effector molecule of atherogenesis at the locus. One focus of this review is the shift in understanding that genetic variation at Chr9p21 not only affects the abundance of , and in some cases expression of the adjacent tumor suppressors, but also impacts splicing, such that 3'-5'-linked circular noncoding RNA species are produced. We describe how the balance of linear and circular RNA, determined by the Chr9p21 genotype, regulates molecular pathways and cellular functions involved in atherogenesis. We end with an outlook on how manipulating circular abundance may be exploited for therapeutic purposes.
自从首次针对冠状动脉疾病（CAD）开展全基因组关联研究（GWAS）以来，9号染色体短臂21区（Chr9p21）风险位点已成为动脉粥样硬化性心血管疾病（包括中风和外周动脉疾病）GWAS中的最强信号。Chr9p21上的CAD风险单核苷酸多态性（SNP）位于一段58千碱基的非蛋白质编码DNA内，其中包含长链非编码RNA（lncRNA）的基因体。Chr9p21位点在分子层面如何影响风险仍是一个正在研究的问题。在此，我们将综述在理解 作为该位点动脉粥样硬化关键风险效应分子方面的最新进展。本综述的一个重点是认识上的转变，即Chr9p21的基因变异不仅影响 的丰度，在某些情况下还影响相邻肿瘤抑制因子的表达，而且还会影响 的剪接，从而产生3'-5'连接的环状非编码RNA种类。我们描述了由Chr9p21基因型决定的线性和环状RNA的平衡如何调节参与动脉粥样硬化的分子途径和细胞功能。最后，我们展望了如何利用调控环状RNA丰度来实现治疗目的。
