Coronary plaque changes with statin and colchicine among people with high polygenic risk- a mechanistic pilot study

项目摘要 冠状动脉疾病(CAD)的全基因组多基因评分识别出20%的人群具有更多的 而不是平均风险的两倍。这些人还没有通过临床风险因素或家族史来确定。 他们从低密度脂蛋白降胆固醇疗法中获得了最大的相对和绝对好处。 在临床上使用多基因评分预防冠心病的一个关键障碍是缺乏前瞻性的实施 多基因高危人群冠状动脉粥样硬化的量化和特征研究 使用药物干预来逆转它。低密度脂蛋白-胆固醇途径只占一小部分 风险，以及其他机制，如炎症，是感兴趣的。小剂量的秋水仙碱已被证明可以 降低稳定性冠状动脉疾病患者心血管事件的风险，但确切的 秋水仙碱如何影响冠状动脉斑块的机制尚不清楚。 我们的建议解决了这些差距，并利用了基因组医学、生物库数据和 冠状动脉成像用于斑块定性，通过基因组医学实施研究回归 结果给医院生物库参与者，随后进行瑞舒伐他汀和秋水仙碱的机械性临床试验 在无创冠状动脉CT血管成像(CCTA)中使用生物标志物和冠状动脉斑块表型。 我们已经从我们的医院生物库中确定了一个由数千人组成的目标人群 他们没有已知的心血管疾病，没有接受降脂或抗炎治疗，并且有 高多基因得分定义为前20%的分布。在AIM1中，我们将返回高多基因风险分数 对300名参与者的结果，并评估基线和一年的心血管健康状况 来自MGH初级保健队列的小组。在AIM2中，我们将测量脂质和炎症生物标记物和 对300名参与者进行CCTA，以研究冠状动脉斑块体积和高危特征，以及他们的 高血压病患者与心血管健康及血脂和炎症生物标记物的相关性 多基因风险。在AIM3中，我们将确定他汀类药物和小剂量秋水仙碱联合治疗是否- 与单独使用他汀类药物相比-有利于调节冠状动脉粥样硬化的进展和成分 在一项对150名参与者进行的机械性先导研究中，多基因得分较高的个体进行了为期一年的跟踪调查。这 这项研究将为识别、披露和逆转亚临床冠状动脉粥样硬化提供一个框架 多基因风险高的个体，并告知低剂量秋水仙碱减少的机制 冠状动脉斑块纵向表型的心血管事件。

Project Summary Genome-wide polygenic score for coronary artery disease (CAD) identifies 20% of the population with more than double the average risk. Those individuals are not identified by clinical risk factors or family history, yet they derive the greatest relative and absolute benefit from LDL-cholesterol lowering therapy. A key barrier to the use of polygenic score in clinic to prevent CAD is the lack of prospective implementation studies that quantify and characterize coronary atherosclerosis in individuals with high polygenic risk and reverse it using pharmacological interventions. LDL-cholesterol pathways account for only a small proportion of risk, and other mechanisms such as inflammation are of interest. Low dose colchicine has been shown to reduce the risk of cardiovascular evens in patients with stable coronary artery disease, but the exact mechanism of how colchicine affects coronary plaque is unknown. Our proposal addresses those gaps and leverages recent innovations in genomic medicine, biobank data, and coronary imaging for plaque characterization, through a genomic medicine implementation study of returning results to hospital biobank participants followed by a mechanistic clinical trial of rosuvastatin and colchicine using biomarkers and coronary plaque phenotypes on noninvasive coronary CT angiography (CCTA). We already identified a target population from our hospital biobank consisting of several thousand individuals who have no known cardiovascular disease, are not on lipid lowering or anti-inflammatory therapy, and have a high polygenic score defined as top 20% of the distribution. In AIM1, we will return a high polygenic risk score result to 300 participants and assess baseline and one-year cardiovascular health compared to a matched group from the MGH Primary Care Cohort. In AIM2, we will measure lipid and inflammatory biomarkers and perform CCTA on the 300 participants to study coronary plaque volumes and high-risk features, and their association with cardiovascular health and lipid and inflammatory biomarkers among individuals with high polygenic risk. In AIM3, we will determine if combination therapy with statin and low dose colchicine – compared with statin alone – favorably modulates progression and composition of coronary atherosclerosis in individuals with high polygenic score in a mechanistic pilot study of 150 participants followed for one year. This study will provide a framework for identification, disclosure, and reversal of subclinical coronary atherosclerosis in individuals with high polygenic risk and inform the mechanism by which low dose colchicine reduces cardiovascular events through longitudinal phenotyping of coronary plaque.