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

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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.