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确定了20%的人群具有更多 平均风险的两倍。这些个体尚未通过临床风险因素或家族史确定， 他们从LDL-胆固醇降低疗法中获得最大的相对和绝对益处。 在临床上使用多基因评分预防CAD的一个关键障碍是缺乏前瞻性实施 在具有高多基因风险的个体中量化和表征冠状动脉粥样硬化的研究， 用药物干预来逆转它。LDL-胆固醇途径只占一小部分， 风险和其他机制，如炎症是感兴趣的。低剂量秋水仙碱已被证明， 降低稳定型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。 我们的提案解决了这些差距，并利用了基因组医学、生物库数据和 冠状动脉成像斑块表征，通过基因组医学实施研究返回 对医院生物样本库参与者进行瑞舒伐他汀和秋水仙碱机制临床试验的结果 在无创冠状动脉CT血管造影（CCTA）上使用生物标志物和冠状动脉斑块表型。 我们已经从我们医院的生物库中确定了一个目标人群， 没有已知的心血管疾病，没有接受降脂或抗炎治疗， 高多基因得分定义为分布的前20%。在AIM 1中，我们将返回高多基因风险评分 结果300名参与者和评估基线和一年的心血管健康相比， MGH初级保健队列的一组。在AIM 2中，我们将测量脂质和炎症生物标志物， 对300名参与者进行CCTA，研究冠状动脉斑块体积和高危特征， 高脂血症患者心血管健康与脂质和炎症生物标志物的相关性 多基因风险在AIM 3中，我们将确定他汀类药物和低剂量秋水仙碱的联合治疗是否- 与单独使用他汀类药物相比， 在对150名参与者进行为期一年的机制试点研究中，对具有高多基因得分的个体进行了跟踪。这 这项研究将为亚临床冠状动脉粥样硬化的识别、揭示和逆转提供一个框架 在具有高多基因风险的个体中，并告知低剂量秋水仙碱降低 通过冠状动脉斑块的纵向表型分析来评估心血管事件。

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.