Molecular and microbial drivers of atherosclerosis

Title [en]

Abstract [sv]

Background:Atherosclerosis is the main pathological mechanism underlying myocardial infarction and ischemic stroke.The project builds on the recent completion of the world-unique cardiovascular imaging study Swedish CArdio Pulmonary Bio Image Study (SCAPIS) and recent technological break-troughs in analytical chemistry and sequencing technology. It is the worlds first project to combine detailed information from vascular imaging in a large population aged 50-64 with non-targeted mass-spectrometry-based metabolomics, genotype data and metagenome shotgun sequencing of intestinal microbiota to identify possible targets for early intervention of cardiovascular disease.Aim:The overall aim of the project is to identify novel targets for early intervention of cardiovascular disease by identifying circulating metabolites that contribute to atherosclerosis and their potential origin in the intestinal microbiota.Work plan:The project has three components:1.We will screen ~1,000 metabolites in 5,000 individuals from the SCAPIS-Uppsala cohort for links with atherosclerosis with replication in 3,000 individuals from the SCAPIS-Malmö cohort; and assessment of the longitudinal development in a subset of SCAPIS-Umeå/VHS cohort (n=400) and incident myocardial infarction (~900 events) and ischemic stroke (~500 events) in SCAPIS, MIMI and SIMPLER to identify metabolites linked to the different stages of atherosclerosis development.2.We will use machine learning to identify the intestinal microbiota components that are associated with these atherosclerosis-linked metabolites in 8,000 individuals3.We will apply network Mendelian Randomization methods based on novel genetic instruments and metabolite perturbation in mice to map the causal network of microbiota, metabolites and atherosclerosis and prioritise candidate targets.Significance:The anticipated outcome of this project will be a set of strong candidate targets for early intervention of cardiovascular disease, which I plan to take forward to drug development.

Abstract [en]

Background:Atherosclerosis is the main pathological mechanism underlying myocardial infarction and ischemic stroke.The project builds on the recent completion of the world-unique cardiovascular imaging study Swedish CArdio Pulmonary Bio Image Study (SCAPIS) and recent technological break-troughs in analytical chemistry and sequencing technology. It is the worlds first project to combine detailed information from vascular imaging in a large population aged 50-64 with non-targeted mass-spectrometry-based metabolomics, genotype data and metagenome shotgun sequencing of intestinal microbiota to identify possible targets for early intervention of cardiovascular disease.Aim:The overall aim of the project is to identify novel targets for early intervention of cardiovascular disease by identifying circulating metabolites that contribute to atherosclerosis and their potential origin in the intestinal microbiota.Work plan:The project has three components:1.We will screen ~1,000 metabolites in 5,000 individuals from the SCAPIS-Uppsala cohort for links with atherosclerosis with replication in 3,000 individuals from the SCAPIS-Malmö cohort; and assessment of the longitudinal development in a subset of SCAPIS-Umeå/VHS cohort (n=400) and incident myocardial infarction (~900 events) and ischemic stroke (~500 events) in SCAPIS, MIMI and SIMPLER to identify metabolites linked to the different stages of atherosclerosis development.2.We will use machine learning to identify the intestinal microbiota components that are associated with these atherosclerosis-linked metabolites in 8,000 individuals3.We will apply network Mendelian Randomization methods based on novel genetic instruments and metabolite perturbation in mice to map the causal network of microbiota, metabolites and atherosclerosis and prioritise candidate targets.Significance:The anticipated outcome of this project will be a set of strong candidate targets for early intervention of cardiovascular disease, which I plan to take forward to drug development.

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