GWAS Reveal Targets in Vessel Wall Pathways to Treat Coronary Artery Disease.
GWAS Reveal Targets in Vessel Wall Pathways to Treat Coronary Artery Disease.
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DOI：
10.3389/fcvm.2018.00072
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发表时间：
2018
影响因子：
3.6
通讯作者：
Miller CL
中科院分区：
文献类型：
--
作者：
Turner AW;Wong D;Dreisbach CN;Miller CL
冠状动脉疾病（CAD）是全球死亡的主要原因，并造成相当大的公共卫生负担。最近的全基因组关联研究（GWAS）已经揭示了与人类CAD易感性相关的>100个遗传基因座。虽然这些基因座中的许多含有目前批准的疗法的基因靶点，例如他汀类药物和PCSK 9抑制剂，但这些基因座处的大多数注释基因编码参与血管壁功能的蛋白质，而没有已知的药物可用。重要的是，许多与血管（平滑肌、内皮和巨噬细胞）细胞过程相关的基因现在被组织成不同的功能途径，例如，血管舒张、生长因子反应、细胞外基质和斑块重塑以及炎症。在这篇简短的综述中，我们重点介绍了最近发现的在血管壁中具有预测作用的基因座，并为现有疗法以及从GWAS获得的新药物靶点提供遗传背景。随着针对这些途径的新模式的发展，（例如，反义寡核苷酸、CRISPR/Cas9和RNA干扰）以及计算框架来优先考虑或重新定位治疗方法，对于受这种常见疾病影响的许多患者来说，有很大的机会缩小从最初的遗传发现到临床转化的差距。
Coronary artery disease (CAD) is the leading cause of mortality worldwide and poses a considerable public health burden. Recent genome-wide association studies (GWAS) have revealed >100 genetic loci associated with CAD susceptibility in humans. While a number of these loci harbor gene targets of currently approved therapies, such as statins and PCSK9 inhibitors, the majority of the annotated genes at these loci encode for proteins involved in vessel wall function with no known drugs available. Importantly many of the associated genes linked to vascular (smooth muscle, endothelial, and macrophage) cell processes are now organized into distinct functional pathways, e.g., vasodilation, growth factor responses, extracellular matrix and plaque remodeling, and inflammation. In this mini-review, we highlight the most recently identified loci that have predicted roles in the vessel wall and provide genetic context for pre-existing therapies as well as new drug targets informed from GWAS. With the development of new modalities to target these pathways, (e.g., antisense oligonucleotides, CRISPR/Cas9, and RNA interference) as well as the computational frameworks to prioritize or reposition therapeutics, there is great opportunity to close the gap from initial genetic discovery to clinical translation for many patients affected by this common disease.